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• Hagl 2016 Nutr Neurosci  + (Aging represents a major risk factor for n … Aging represents a major risk factor for neurodegenerative diseases such as Alzheimer's disease. Mitochondria are significantly involved in both the aging process and neurodegeneration. One strategy to protect the brain and to prevent neurodegeneration is a healthy lifestyle including a diet rich in antioxidants and polyphenols. Rice bran extract (RBE) contains various antioxidants including natural vitamin E forms (tocopherols and tocotrienols) and gamma-oryzanol. In this work, we examined the effects of a stabilized RBE on mitochondrial function in 18-month-old Naval Medical Research Institute mice (340 mg/kg body weight/day), which received the extract for 3 weeks via oral gavage.</br></br>Mitochondrial parameters were measured using high-resolution respirometry (Oroboros Oxygraph-2k), Western blot analysis, and photometric methods in dissociated brain cells, isolated mitochondria, and brain homogenate. Vitamin E concentrations in blood plasma and brain tissue were measured using HPLC with fluorescence detection. </br></br>Aging leads to decreased mitochondrial function (decreased mitochondrial respiration and ATP production) and decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha). RBE administration increased alpha-tocopherol concentrations in the brain and compensated for age-related mitochondrial dysfunction by increasing mitochondrial respiration, membrane potential, PGC1alpha protein expression, and citrate synthase activity. Furthermore, resistance of brain cells to sodium nitroprusside-induced nitrosative stress was improved. </br></br>According to these results, RBE is a promising candidate nutraceutical for the prevention of age-related neurodegenerative diseases.of age-related neurodegenerative diseases.)
• Hagl 2016 Neuromolecular Med  + (Aging represents a major risk factor for t … Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer's disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction ''in vitro'' and in short-term ''in vivo'' feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD.nd thereby delaying or even preventing AD.)
• Reutzel 2018 Oxid Med Cell Longev  + (Aging represents a major risk factor for d … Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer's disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.ergy metabolism in the brain of aged mice.)
• Lee 2010 Cell Metab  + (Aging-associated muscle insulin resistance … Aging-associated muscle insulin resistance has been hypothesized to be due to decreased mitochondrial function, secondary to cumulative free radical damage, leading to increased intramyocellular lipid content. To directly test this hypothesis, we examined both ''in vivo'' and ''in vitro'' mitochondrial function, intramyocellular lipid content, and insulin action in lean healthy mice with targeted overexpression of the human catalase gene to mitochondria (MCAT mice). Here, we show that MCAT mice are protected from age-induced decrease in muscle mitochondrial function (∼30%), energy metabolism (∼7%), and lipid-induced muscle insulin resistance. This protection from age-induced reduction in mitochondrial function was associated with reduced mitochondrial oxidative damage, preserved mitochondrial respiration and muscle ATP synthesis, and AMP-activated protein kinase-induced mitochondrial biogenesis. Taken together, these data suggest that the preserved mitochondrial function maintained by reducing mitochondrial oxidative damage may prevent age-associated whole-body energy imbalance and muscle insulin resistance.y imbalance and muscle insulin resistance.)
• Cockova 2017 Thesis  + (Aim of this thesis was to observe changes … Aim of this thesis was to observe changes in oxidative metabolism and expression of important neuroenergetic proteins in human neuroblastoma cell line SH-SY5Y due to inhibition of FTO. FTO is a RNA demethylase that uses N6-methyladenosine as substrate. Differences in enzyme expression are connected to a broad area of effects involving energy homeostasis.</br></br>Mitochondria are the cellular powerhouses, a key elements in production of energy and metabolic substrates, yet a source of potentially dangerous reactive oxygen species (ROS) and analogous reactive molecules. In order to better understand FTO purpose in neuronal energetic metabolism, we examined mitochondrial respiratory chain. Using high-resolution respirometry we were capable of observing impairment in mitochondrial respiration after FTO inhibition. There was a considerable decline in endogenous respiration, maximal respiration rate and reserve capacity. In order to obtain a more detailed view into mitochondrial respiration, expression levels of electron-transport complexes were quantified by Western blot technique. A slight reduction was identified in subunits of complex I and IV. However, the most prominent alteration was seen in the complex II subunit. There were no differences in expression of complex III and ATP synthase subunits. Beside disrupted activity of electron-transport system, ROS production can reflect mitochondrial dysfunction. By using fluorescence probes, we managed to observe increased ROS production in cells treated with FTO inhibitor.</br></br>Furthermore, we studied how FTO inhibition affects insulin signaling. Expression of selected proteins involved in insulin signaling was detected by Western blot. Increased levels of insulin receptor and insulin degrading enzyme accompanied FTO inhibition. Additionally, a decreased ratio of p-Akt/Akt and p-p38/p38 together with an elevated ratio of p-ERK/ERK was observed. A minimal difference was sighted in PI3K p110 expression or p-GSK3β/GSK3β ratio.</br></br>Taken together, these results suggest a considerable link between FTO activity and neuronal signaling and metabolic actions. Further research could undoubtedly prove to be beneficial in gaining knowledge about bioenergetics processes in the nervous system.nergetics processes in the nervous system.)
• Larsen 2009 Diabetologia  + (Aim/hypothesis: The aim of the study was t … Aim/hypothesis: The aim of the study was to investigate mitochondrial function, fibre type distribution and substrate oxidation in arm and leg muscle during exercise in patients with type 2 diabetes and in obese and lean controls.Methods: Indirect calorimetry was used to calculate fat and carbohydrate oxidation during both progressive arm-cranking and leg-cycling exercises. Muscle biopsies from arm and leg were obtained. Fibre type, as well as O₂ flux capacity of saponin-permeabilised muscle fibres were measured, the latter by high resolution respirometry, in patients with type 2 diabetes, age- and BMI-matched obese controls, and age-matched lean controls.Results: Fat oxidation was similar in the groups during either arm or leg exercise. During leg exercise at higher intensities, but not during arm exercise, carbohydrate oxidation was lower in patients with type 2 diabetes compared with the other groups. In patients with type 2 diabetes, ADP-stimulated state 3 respiration per mg muscle with parallel electron input from complex I+II was lower in ''m. vastus lateralis'' compared with obese and lean controls, whereas no differences between groups were present in ''m. deltoideus''. A higher percentage of type IIX fibres was seen in ''m. vastus lateralis'' in patients with type 2 diabetes compared with obese and lean controls, whereas no difference was found in the deltoid muscle.Conclusions/interpretation: This study demonstrates similar O₂ flux capacity, fibre type distribution and carbohydrate oxidation in arm muscle in the groups despite the presence of attenuated values in leg muscle in patients with type 2 diabetes compared with obese and lean controls.tients with type 2 diabetes compared with obese and lean controls.)
• Raboel 2009 J Clin Endocrinol Metabol  + (Aim: Skeletal muscle mitochondrial content … Aim: Skeletal muscle mitochondrial content is reduced in type 2 diabetes mellitus (T2DM). Whether hyperglycemia inhibits mitochondrial biogenesis and/or function is unknown. This study examined the effect of different levels of glycemia on skeletal muscle mitochondrial function in patients with T2DM.</br></br>Patients and Methods: Eleven patients with T2DM [9 males, 2 females; age, 52.8 ± 2.5 yr (mean ± SE); body mass index, 30.2 ± 1.1 kg/m² ] in poor glycemic control were treated with insulin aspart and NPH insulin for a median period of 46 d (range, 31–59). Mitochondrial respiration and citrate synthase activity (a marker of mitochondrial content) were measured before and after treatment. Eleven healthy subjects (age, 53.3 ± 2.7 yr; body mass index, 30.6 ± 1.1 kg/m2) were included as controls.</br></br>Results: Hemoglobin A1c (9.1 ± 0.5 to 7.5 ± 0.3%; P < 0.001) and fasting plasma glucose (12.7 ± 1.1 to 6.5 ± 0.3 mmol/liter; P < 0.001) were reduced after treatment. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls [substrates for complex I, 24% lower (P < 0.05); substrates for complex I+II, 17% lower (P < 0.05)]. Mitochondrial respiration and citrate synthase activity did not differ before and after improvements in glycemic control, but mitochondrial respiration correlated with fasting plasma glucose before (r² = 0.53; P < 0.05) but not after treatment [r² = 0.0024; not significant (NS)]. Mitochondrial respiration normalized to mitochondrial content did not differ between control subjects and patients with T2DM.</br></br>Discussion: Mitochondrial respiration and content was not improved after significant improvements in glycemic control. However, severe hyperglycemia inhibited respiration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.ration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.)
• Baron 2010 Thesis  + (Aim: The aim of this thesis was the analys … Aim: The aim of this thesis was the analysis of copy number variations of the</br>mitochondrial DNA (mtDNA) in several tissues and cell types with regard to different mitochondrial associated disorders.</br>Background: The mtDNA copy number can be reduced due to mutations in the</br>nuclear encoded DNA polymerase g (POLG) or damages caused by deleterious</br>reactive oxygen species (ROS), which are created by the respiratory chain. This</br>leads to the insufficient expression of mitochondrial encoded subunits of complexes of the oxidative phosphorylation system (OXPHOS). Consequently an impairment of the biochemical activity and integrity of the cells occurs.</br>Methods: The quantification of the mtDNA was performed by quantitative PCR</br>(qPCR). Biochemical activities were determined by enzymatic assays such as direct measurement of the citrate synthase (CS) activity or comprehensive measurement of the respiratory activity.</br>Results: Mutations in the nuclear inherited gene POLG result in mtDNA depletion in mitochondrial disorders including a mild phenotype of progressive external</br>ophthalmoplegia (PEO) with epilepsy/ataxia. A mtDNA depletion was detected in</br>different tissues and cell types of Alpers-Huttenlocher patients with pathogenic</br>nuclear mutations. The mtDNA copy number was reduced in specific hippocampal</br>regions of temporal lobe epilepsy (TLE) patients with Ammons’ horn sclerosis (AHS)accompanied by a decreased CS activity. An ''in vitro'' reduction of the mtDNA in fibroblasts results in an impaired respiratory activity.</br>Conclusions: The mtDNA content is proportional to the mitochondria content and</br>the energy demand of the respective tissue or cell type under normal conditions. A cell type- and tissue-specific depletion of the mtDNA can be present in several inherited and somatic mitochondrial disorders ''in vivo'' or can be generated by an ''in vitro'' system. The mtDNA depletion diminishes the biochemical activity and integrity of the cells and can contribute to the disease phenotype.d can contribute to the disease phenotype.)
• Lai 2019 Acta Physiol (Oxf)  + (Aim: The subsarcolemmal (SSM) and interfib … Aim: The subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in skeletal muscle appear to have distinct biochemical properties affecting metabolism in health and disease. The isolation of mitochondrial subpopulations has been a long-time challenge while the presence of a continuous mitochondrial reticulum challenges the view of distinctive SSM and IFM bioenergetics. Here, a comprehensive approach is developed to identify the best conditions to separate mitochondrial fractions.</br></br>Methods: The main modifications to the protocol to isolate SSM and IFM from rat skeletal muscle were: (a) decreased dispase content and homogenization speed; (b) trypsin treatment of SSM fractions; (c) recentrifugation of mitochondrial fractions at low speed to remove subcellular components. To identify the conditions preserving mitochondrial function, integrity, and maximizing their recovery, microscopy (light and electron) were used to monitor effectiveness and efficiency in separating mitochondrial subpopulations while respiratory and enzyme activities were employed to evaluate function, recovery, and integrity.</br></br>Results: With the modifications described, the total mitochondrial yield increased with a recovery of 80% of mitochondria contained in the original skeletal muscle sample. The difference between SSM and IFM oxidative capacity (10%) with complex-I substrate was significant only with a saturated ADP concentration. The inner and outer membrane damage for both subpopulations was <1% and 8%, respectively, while the respiratory control ratio was 16.</br></br>Conclusion: Using a multidisciplinary approach, conditions were identified to maximize SSM and IFM recovery while preserving mitochondrial integrity, biochemistry, and morphology. High quality and recovery of mitochondrial subpopulations allow to study the relationship between these organelles and disease.ionship between these organelles and disease.)
• Hedges IBEC2012  + (Aim: This study aimed to compare mitochond … Aim: This study aimed to compare mitochondrial oxygen consumption </br>in C57BL/6J wild-type and myostatin-deficient mouse soleus and white </br>gastrocnemius muscles.</br></br>Methods: Muscles were obtained from 4 month-old male mice. Mass-specific oxygen consumption (pmol.O2/mg/sec) was measured in </br>permeabilised muscle, using high-resolution respirometry (Oroboros </br>Oxygraph-2k). Maximal activities of citrate synthase and lactate </br>dehydrogenase were determined by spectrophotometry.</br></br>Results: Myostatin-deficient soleus (n=6) consumed 20% more oxygen </br>per mg than wild-type soleus (n=6) during oxidative phosphorylation. This </br>was accompanied by greater citrate synthase and lactate dehydrogenase </br>enzyme activity in myostatin-deficient soleus (29% and 80% respectively). </br>Myostatin-deficient gastrocnemius (n=7) showed 26% lower oxygen </br>consumption during uncoupled respiration, and 34% lower oxygen </br>consumption when oxidising glycerol-3-phosphate compared to wild-type gastrocnemius (n=8). Citrate synthase activity was not significantly </br>different and lactate dehydrogenase activity 26% greater in myostatin-deficient gastrocnemius compared to wild-type gastrocnemius.</br></br>Conclusion: These data suggest that myostatin-deficiency exerts fiber-type specific effects on skeletal muscle mitochondrial function.on skeletal muscle mitochondrial function.)
• Chu SRS 2011  + (Aim: To determine the impact of cold ischa … Aim: To determine the impact of cold ischaemia on hepatic mitochondrial function in University of Wisconsin (UW) solution in the setting of hepatic steatosis.</br></br>Methods: Livers were harvested from 10-week old genetically obese (ob/ob, ''n'' = 9) or lean C57 control mice (''n'' = 9); and preserved in ice-cold UW solution. Mitochondrial function analysis was performed on permeabilised liver samples using a substrate and inhibitor titration protocol in conjunction with a high-resolution respirometer (OROBOROS® Oxygraph-2k) at multiple time-points over 24 h during cold ischemia (CI).</br></br>Results: Ob/ob mice livers and control mice livers showed either severe (> 60%) or no macrovesicular steatosis respectively. Mitochondria from ob/ob mice livers demonstrated a faster and greater decrease in the percentage of respiration contributing to oxidative phosphorylation over 24 hours of cold storage compared to control mice. After 12 hours of CI, there was also an increased dependence on Complex II respiration relative to Complex I in ob/ob mice livers suggestive of Complex I damage and potential loss of key ATP synthesis efficiency.</br></br>Conclusion: There was a time-dependant damage of hepatic mitochondrial function during CI. Steatotic livers demonstrated greater mitochondrial dysfunction during CI compared to lean livers.ysfunction during CI compared to lean livers.)
• Bakkman 2007 ActaPhysiol  + (Aim: To investigate if training during hyp … Aim: To investigate if training during hypoxia (H) improves the adaptation of muscle oxidative function compared with normoxic (N) training performed at the same relative intensity.</br></br>Method: Eight untrained volunteers performed one-legged cycle training during 4 weeks in a low-pressure chamber. One leg was trained under N conditions and the other leg under hypobaric hypoxia (526 mmHg) at the same relative intensity as during N (65% of maximal power output, ''W''_max). Muscle biopsies were taken from vastus lateralis before and after the training period. Muscle samples were analysed for the activities of oxidative enzymes [citrate synthase (CS) and cytochrome c oxidase (COX)] and mitochondrial respiratory function.</br></br>Results: ''W''_max increased with more than 30% over the training period during both N and H. CS activity increased significantly after training during N conditions (+20.8%, P < 0.05) but remained unchanged after H training (+4.5%, ns) with a significant difference between conditions (''P'' < 0.05 H vs. N). COX activity was not significantly changed by training and was not different between exercise conditions [+14.6 (N) vs. -2.3% (H), ns]. Maximal ADP stimulated respiration (state 3) expressed per weight of muscle tended to increase after N (+31.2%, ''P'' < 0.08) but not after H training (+3.2%, ns). No changes were found in state four respiration, respiratory control index, P/O ratio, mitochondrial Ca2+ resistance and apparent ''K''m for oxygen.</br></br>Conclusion: The training-induced increase in muscle oxidative function observed during N was abolished during H. Altitude training may thus be disadvantageous for adaptation of muscle oxidative function.ng may thus be disadvantageous for adaptation of muscle oxidative function.)
• Cour 2014 J Cardiovasc Pharmacol Ther  + (Aim: To investigate whether slight variati … Aim: To investigate whether slight variations in core temperature prior to cardiac arrest (CA) influence short-term outcomes and mitochondrial functions.</br></br>Three groups of New Zealand White rabbits (n = 12/group) were submitted to 15 minutes of CA at 38°C (T-38 group), 39°C (T-39), or 40°C (T 40) and 120 minutes of reperfusion. A Sham-operated group (n = 6) underwent only surgery. Restoration of spontaneous circulation (ROSC), survival, hemodynamics, and pupillary reactivity were recorded. Animals surviving to the end of the observation period were euthanized to assess fresh brain and heart mitochondrial functions (permeability transition and oxidative phosphorylation). Markers of brain and heart damages were also measured.</br></br>The duration of asphyxia required to induce CA was significantly lower in the T-40 group when compared to the T-38 group (''p''<.05). The rate of ROSC was >80% in all groups (''p''=nonsignificant [ns]). Survival significantly differed among the T-38, T-39, and T-40 groups: 10 (83%) of 12, 7 (58%) of 12, and 4 (33%) of 12, respectively (log-rank test, ''p''=.027). At the end of the protocol, none of the animals in the T-40 group had pupillary reflexes compared to 8 (67%) of 12 in the T-38 group (''p''<.05). Troponin and protein S100B were significantly higher in the T-40 versus T-38 group (''p''<.05). Cardiac arrest significantly impaired both inner mitochondrial membrane integrity and oxidative phosphorylation in all groups. Brain mitochondria disorders were significantly more severe in the T-40 group compared to the T-38 group (''p''< .05).</br></br>Small changes in body temperature prior to asphyxial CA significantly influence brain mitochondrial functions and short-term outcomes in rabbits.tochondrial functions and short-term outcomes in rabbits.)
• Orynbayeva 2015 Nanomedicine (Lond)  + (Aim: To successfully translate magneticall … Aim: To successfully translate magnetically mediated cell targeting from bench to bedside, there is a need to systematically assess the potential adverse effects of magnetic nanoparticles (MNPs) interacting with ‘therapeutic’ cells. Here, we examined in detail the effects of internalized polymeric MNPs on primary rat endothelial cells’ structural intactness, metabolic integrity and proliferation potential.</br></br>Materials & methods: The intactness of cytoskeleton and organelles was studied by fluorescent</br>confocal microscopy, flow cytometry and high-resolution respirometry. Results: MNPloaded primary endothelial cells preserve intact cytoskeleton and organelles, maintain normal rate of proliferation, calcium signaling and mitochondria energy metabolism.</br></br>Conclusion: This study provides supportive evidence that MNPs at doses necessary</br>for targeting did not induce significant adverse effects on structural integrity and functionality of primary endothelial cells – potential cell therapy vectors.helial cells – potential cell therapy vectors.)
• Doerrier 2014 Life Sci  + (Aims. Previous data showed that melatonin … Aims. Previous data showed that melatonin maintains liver mitochondrial homeostasis during sepsis, but neither the mechanisms underlying mitochondrial dysfunction nor the target of melatonin are known.</br></br>Main methods. Here, we analyzed mitochondrial respiration in isolated mouse liver mitochondria with different substrate combinations (glutamate/malate, glutamate/malate/sucinate or succinate/rotenone) to identify mitochondrial defects and melatonin targets during sepsis. Other bioenergetic parameters including a + a3, b, and c + c1 content, mitochondrial mass, and mitochondrial supercomplexes formation were analyzed. Mitochondrial function was assessed during experimental sepsis induced by cecal ligation and puncture (CLP) in livers of 3 mo. C57BL/6 mice at early and late phases of sepsis, i.e., at 8 and 24 h after sepsis induction.</br></br>Key findings. Septic mice showed mitochondrial injury with a decrease in state 3, respiratory control rate, mitochondrial mass, and cytochrome b and c + c1 content, which was prevented by melatonin treatment. Mitochondrial dysfunction in sepsis was mainly linked to complex I damage, because complex II was far less impaired. These mitochondria preserved the respiratory supramolecular organization, maintaining their electron transport system capacity.</br></br>Significance. This work strengthens the use of substrate combinations to identify specific respiratory defects and selective melatonin actions in septic mitochondria. Targeting mitochondrial complex I should be a main therapeutical approach in the treatment of sepsis, whereas the use of melatonin should be considered in the therapy of clinical sepsis.sidered in the therapy of clinical sepsis.)
• Boushel 2007 Diabetologia  + (Aims/hypothesis: Insulin resistance and ty … Aims/hypothesis: Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content.</br>Materials and methods: The O₂ flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (''n''=8; age 58±2 years [mean±SEM]; BMI 28±1 kg/m²; fasting plasma glucose 5.4±0.2 mmol/l) and patients with type 2 diabetes (''n''=11; age 62±2 years; BMI 32±2 kg/m²; fasting plasma glucose 9.0±0.8 mmol/l) was measured by high-resolution respirometry.</br></br>Results: O₂ flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower ( ''p''<0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31±2 vs 43±3 pmol O₂ s^-1 mg^-1) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63±3 vs 85±6 pmol s^-1 mg^-1). Further increases in O₂ flux capacity were observed in response to uncoupling by FCCP, but were again lower ( ''p''<0.05) in type 2 diabetic patients than in healthy control subjects (86±4 vs 109±8 pmol s^-1 mg^-1). However, when O₂ flux was normalised for mitochondrial DNA content or citrate synthase activity,there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects.</br></br>Conclusions/interpretation: Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.Conclusions/interpretation: Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.)
• Winnica 2019 Antioxid Redox Signal  + (Aims: Asthma, characterized by airway obst … Aims: Asthma, characterized by airway obstruction and hyper-responsiveness, is more severe and less responsive to treatment in obese subjects. While alterations in mitochondrial function and redox signaling have been implicated in asthma pathogenesis, it is unclear whether these mechanisms differ in lean versus obese asthmatics. In addition, we previously demonstrated that circulating platelets from asthmatic individuals have altered bioenergetics; however, it is unknown whether platelet mitochondrial changes reflect those observed in airway epithelial cells. Herein we hypothesized that lean and obese asthmatics show differential bioenergetics and redox signaling in airway cells and that these alterations could be measured in platelets from the same individual. </br></br>Results: Using freshly isolated bronchial airway epithelial cells and platelets from lean and obese asthmatics and healthy individuals, we show that both cell types from obese asthmatics have significantly increased glycolysis, basal and maximal respiration, and oxidative stress compared with lean asthmatics and healthy controls. This increased respiration was associated with enhanced arginine metabolism by arginase, which has previously been shown to drive respiration. Inducible nitric oxide synthase (iNOS) was also upregulated in cells from all asthmatics. However, due to nitric oxide synthase uncoupling in obese asthmatics, overall nitric oxide (NO) bioavailability was decreased, preventing NO-dependent inhibition in obese asthmatic cells that was observed in lean asthmatics. </br></br>Innovation and Conclusion: These data demonstrate bioenergetic differences between lean and obese asthmatics that are, in part, due to differences in NO signaling. They also suggest that the platelet may serve as a useful surrogate to understand redox, oxidative stress and bioenergetic changes in the asthmatic airway.energetic changes in the asthmatic airway.)
• Takada 2016 Cardiovasc Res  + (Aims: Exercise capacity is reduced in hear … Aims: Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI).</br></br>Methods and results: MI was created in male C57BL/6J mice by ligating the left coronary artery, and a sham operation was performed in other mice. The mice were then divided into two groups according to the treatment with or without a DPP-4 inhibitor, MK-0626 [1 mg/kg body weight (BW)/day] provided in the diet. Four weeks later, the exercise capacity evaluated by treadmill test was revealed to be limited in the MI mice, and it was ameliorated in the MI + MK-0626 group without affecting the infarct size or cardiac function. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, supercomplex formation, and their quantity were reduced in the skeletal muscle from the MI mice, and these decreases were normalized in the MI + MK-0626 group, in association with the improvement of mitochondrial biogenesis. Immunohistochemical staining also revealed that a shift toward the fast-twitch fibre type in the MI mice was also reversed by MK-0626. Favourable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Exendin-(9-39) (150 pmol/kg BW/min, subcutaneous osmotic pumps) in MI + MK-0626 mice. Similarly, exercise capacity and mitochondrial function were significantly improved by treatment of GLP-1 agonist, Exendin-4 (1 nmol/kg/BW/h, subcutaneous osmotic pumps).</br></br>Conclusions: A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle.drial biogenesis in their skeletal muscle.)
• Nambu 2021 Cardiovasc Res  + (Aims: Exercise intolerance in patients wit … Aims: Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischaemic tissue. Here, we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production.</br></br>Methods and results: Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analysed. XO-derived ROS production was significantly increased in MI mice from Days 1 to 3 post-surgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham + vehicle (Sham + Veh), MI + vehicle (MI + Veh), and MI + febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI + Feb). Febuxostat or vehicle was administered at 1 and 24 h before surgery, and once-daily on Days 1-7 post-surgery. On Day 28 post-surgery, exercise capacity and mitochondrial respiration in skeletal muscle fibres were significantly decreased in MI + Veh compared with Sham + Veh mice. An increase in damaged mitochondria in MI + Veh compared with Sham + Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibres (higher XO-derived ROS) was reduced via the down-regulation of protein synthesis-associated mTOR-p70S6K signalling in MI + Veh compared with Sham + Veh mice. These impairments were ameliorated in MI + Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function.</br></br>Conclusion: XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF. and exercise intolerance in mice with HF.)
• Doridot 2014 Antioxid Redox Signal  + (Aims: Storkhead Box 1 (STOX1) is a winged- … Aims: Storkhead Box 1 (STOX1) is a winged-helix transcription factor implicated in the genetic forms of a high-prevalence human gestational disease, preeclampsia. STOX1 overexpression confers preeclampsia-like transcriptomic features to trophoblastic cell lines, and preeclampsia symptoms to pregnant mice. The aim of this work was to evaluate the impact of STOX1 on free radical equilibrium and mitochondrial function, ''in vitro'' and ''in vivo''. Results: Transcriptome analysis of STOX1-transgenic versus non-transgenic placentas at 16.5 days of gestation revealed alterations of mitochondria-related pathways. Placentas overexpressing STOX1 displayed altered mitochondrial mass and were severely biased towards protein nitration, indicating nitroso-redox imbalance ''in vivo''. Trophoblast cells overexpressing STOX1 displayed an increased mitochondrial activity at 20% O2 and in hypoxia, despite a reduction of the mitochondrial mass in this situation. STOX1 overexpression is therefore associated to hyperactive mitochondria leading to increased free radical production. Moreover, nitric oxide (NO) production pathways were activated, resulting in peroxynitrite formation. At low oxygen pressure, STOX1 overexpression in the placenta as well as in a trophoblast cell line, switched the free radical balance from Reactive Oxygen Species (ROS) to Reactive Nitrogen Species (RNS). Innovation: In preeclamptic placentas, NO interacts with ROS to generate peroxynitrite and nitrated proteins as end products. This process will deprive the maternal organism of NO, a crucial vasodilator molecule. Conclusion: Our data posit STOX1 as a genetic switch in the ROS/RNS balance and suggest an explanation for elevated blood pressure in preeclampsia.r elevated blood pressure in preeclampsia.)
• Goo 2012 PLoS One  + (Akt, a serine/threonine kinase has been sh … Akt, a serine/threonine kinase has been shown to stimulate glycolysis in cancer cells but its role in mitochondrial respiration is unknown. Using PTEN-knockout mouse embryonic fibroblasts (MEF(PTEN-/-)) with hyper-activated Akt as a cell model, we observed a higher respiratory capacity in MEF(PTEN-/-) compared to the wildtype (MEF(WT)). The respiratory phenotype observed in MEF(PTEN-/-) was reproduced in MEF(WT) by gene silencing of PTEN which substantiated its role in regulating mitochondrial function. The increased activities of the respiratory complexes (RCs) I, III and IV were retained in the same relative proportions as those present in MEF(WT), alluding to a possible co-ordinated regulation by PTEN/Akt. Using LY294002 (a PI3K inhibitor) and Akt inhibitor IV, we showed that the regulation of enzyme activities and protein expressions of the RCs was dependent on PI3K/Akt. There was insignificant difference in the protein expressions of mitochondrial transcription factor: peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and its downstream targets, the nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (mtTFA) between MEF(PTEN-/-) and MEF(WT). Similarly, mRNA levels of the same subunits of the RCs detected in Western blots were not significantly different between MEF(PTEN-/-) and MEF(WT) suggesting that the regulation by Akt on mitochondrial function was probably not via gene transcription. On the other hand, a decrease of total 4E-BP1 with a higher expression of its phosphorylated form relative to total 4E-BP1 was found in MEF(PTEN-/-), which inferred that the regulation of mitochondrial respiratory activities by Akt was in part through this protein translation pathway. Notably, gene silencing of 4E-BP1 up-regulated the protein expressions of all RCs and the action of 4E-BP1 appeared to be specific to these mitochondrial proteins. In conclusion, PTEN inactivation bestowed a bioenergetic advantage to the cells by up-regulating mitochondrial respiratory capacity through the 4E-BP1-mediated protein translation pathway.-BP1-mediated protein translation pathway.)
• Jasz 2021 J Cell Mol Med  + (Albeit previous experiments suggest potent … Albeit previous experiments suggest potential anti-inflammatory effect of exogenous methane (CH₄) in various organs, the mechanism of its bioactivity is not entirely understood. We aimed to investigate the potential mitochondrial effects and the underlying mechanisms of CH₄ in rat cardiomyocytes and mitochondria under simulated ischaemia/reperfusion (sI/R) conditions. Three-day-old cultured cardiomyocytes were treated with 2.2% CH₄ -artificial air mixture during 2-hour-long reoxygenation following 4-hour-long anoxia (sI/R and sI/R + CH₄ , n = 6-6), with normoxic groups serving as controls (SH and SH + CH₄ ; n = 6-6). Mitochondrial functions were investigated with high-resolution respirometry, and mitochondrial membrane injury was detected by cytochrome c release and apoptotic characteristics by using TUNEL staining. CH₄ admixture had no effect on complex II (CII)-linked respiration under normoxia but significantly decreased the complex I (CI)-linked oxygen consumption. Nevertheless, addition of CH₄ in the sI/R + CH₄ group significantly reduced the respiratory activity of CII in contrast to CI and the CH₄ treatment diminished mitochondrial H₂O₂ production. Substrate-induced changes to membrane potential were partially preserved by CH₄ , and additionally, cytochrome c release and apoptosis of cardiomyocytes were reduced in the CH₄ -treated group. In conclusion, the addition of CH₄ decreases mitochondrial ROS generation via blockade of electron transport at CI and reduces anoxia-reoxygenation-induced mitochondrial dysfunction and cardiomyocyte injury ''in vitro''.₄ decreases mitochondrial ROS generation via blockade of electron transport at CI and reduces anoxia-reoxygenation-induced mitochondrial dysfunction and cardiomyocyte injury ''in vitro''.)
• Karadayian 2015 Neuroscience  + (Alcohol hangover (AH) is defined as the te … Alcohol hangover (AH) is defined as the temporary state after alcohol binge-like drinking, starting when ethanol (EtOH) is absent in plasma. Previous data indicate that AH induces mitochondrial dysfunction and free radical production in mouse brain cortex. The aim of this work was to study mitochondrial function and reactive oxygen species production in mouse cerebellum at the onset of AH. Male mice received a single i.p. injection of EtOH (3.8g/kg BW) or saline solution. Mitochondrial function was evaluated 6h after injection (AH onset). At the onset of AH, malate-glutamate and succinate-supported state 4 oxygen uptake was 2.3 and 1.9-fold increased leading to a reduction in respiratory control of 55% and 48% respectively, as compared with controls. Decreases of 38% and 16% were found in Complex I-III and IV activities. Complex II-III activity was not affected by AH. Mitochondrial membrane potential and mitochondrial permeability changes were evaluated by flow cytometry. Mitochondrial membrane potential and permeability were decreased by AH in cerebellum mitochondria. Together with this, AH induced a 25% increase in superoxide anion and a 92% increase in hydrogen peroxide production in cerebellum mitochondria. Related to nitric oxide (NO) metabolism, neuronal nitric oxide synthase (nNOS) protein expression was 52% decreased by the hangover condition compared with control group. No differences were found in cerebellum NO production between control and treated mice. The present work demonstrates that the physiopathological state of AH involves mitochondrial dysfunction in mouse cerebellum showing the long-lasting effects of acute EtOH exposure in the central nervous system.OH exposure in the central nervous system.)
• Wang 2009 Int J Clin Exp Pathol  + (Alcohol use has become far too prevalent i … Alcohol use has become far too prevalent in our society. Alcohol kills 6.5 times more youth than all other illicit drugs combined. In combination with traumatic and hemorrhagic injuries, alcohol results in a much higher mortality rate. Alcohol, alone and in high dosages, also causes great damage to the body, often leading to death as well. Thus, it is of utmost importance that research is conducted to help explain the pathological mechanism of high fatalities and injuries associated with alcohol use. In order to simulate this complex situation in vitro, a rat hepatoma cell line (H-II-4-E) was exposed to various concentrations of ethanol as well as the condition of hypoxia. Hypoxia mimics the primary level of tissue damage caused by hemorrhage after impact in a car accident. In this way, we tested the hypothesis that the presence of ethanol in combination with hypoxia causes greater cellular damage compared to conditions of ethanol or hypoxia alone. Ethanol, alone and in high concentrations, was found to greatly affect cell function as shown by decreased cellular ATP levels, increased LDH release, and a downregulated expression of CYP2E1 gene. By adding the condition of hypoxia to low concentrations of ethanol, cellular damage increased dramatically as well. Decreased gene expression and protein levels of CYP2E1 correlated with increased hepatocyte injury and thus, this enzyme may significantly contribute to the severity of cellular damage. These results provide useful information for future research on the effects of ethanol in combination with hemorrhage on cells in vitro, simulating the condition of driving while intoxicated and binge drinking.ving while intoxicated and binge drinking.)
• Wen 2023 PLoS One  + (Alcoholic myopathy is caused by chronic co … Alcoholic myopathy is caused by chronic consumption of alcohol (ethanol) and is characterized by weakness and atrophy of skeletal muscle. Regular exercise is one of the important ways to prevent or alleviate skeletal muscle myopathy. However, the beneficial effects and the exact mechanisms underlying regular exercise on alcohol myopathy remain unclear. In this study, a model of alcoholic myopathy was established using zebrafish soaked in 0.5% ethanol. Additionally, these zebrafish were intervened to swim for 8 weeks at an exercise intensity of 30% of the absolute critical swimming speed (Ucrit), aiming to explore the beneficial effects and underlying mechanisms of regular exercise on alcoholic myopathy. This study found that regular exercise inhibited protein degradation, improved locomotion ability, and increased muscle fiber cross-sectional area (CSA) in ethanol-treated zebrafish. In addition, regular exercise increases the functional activity of mitochondrial respiratory chain (MRC) complexes and upregulates the expression levels of MRC complexes. Regular exercise can also improve oxidative stress and mitochondrial dynamics in zebrafish skeletal muscle induced by ethanol. Additionally, regular exercise can activate mitochondrial biogenesis and inhibit mitochondrial unfolded protein response (UPRmt). Together, our results suggest regular exercise is an effective intervention strategy to improve mitochondrial homeostasis to attenuate alcoholic myopathy.meostasis to attenuate alcoholic myopathy.)

• ALGAEUROPE 2018 Amsterdam NL  + (AlgaEurope 2018, Amsterdam, Netherlands, 2018)

• AlgaEurope 2020 Virtual Event  + (AlgaEurope 2020, Virtual Event, 2020, NextGen-O2k)
• AlgaEurope 2022 Rome IT  + (AlgaEurope 2022, Rome, IT, 2022)
• Gnaiger 2022 Abstract Bioblast-PB  + (Algal biotechnology has emerged as a high- … Algal biotechnology has emerged as a high-potential industry for efficient and CO₂-neutral production of biomass providing biofuels, food and feed, and a variety of carbon-based chemicals and pharmaceuticals. Algal metabolism is directly involved in the regulation of growth, cell concentration, and biosynthesis of biotechnologically-relevant phytochemicals such as vitamins, antioxidants, and immune response boosters. Photoautotrophic growth rates of algae are based on light-to-chemical energy conversion and CO₂ fixation, and any optimization of biomass production requires maximizing energy-use efficiency of photosynthesis and respiration, both of which vary as a function of light intensity. As such, the bioenergetic crosstalk between mitochondria and chloroplasts plays a key role in maintaining metabolic integrity and controlling intermediary metabolite production. </br></br>In the present study, we investigated how photosynthetic O₂ production and respiratory O₂ consumption was influenced as a function of light intensity, O₂ concentration, and culture density in the unicellular model green alga ''Chlamydomonas reinhardtii''. Cultures were grown photoautotrophically in a modified Tris-Phosphate growth medium (TRIS, N- and P-nutrient replete) at 25 °C, pH 7.0, and light intensity of 100 µmol photons·s^-1·m^-2 (16:8 h light:dark cycle). Kinetics of light-induced O₂ production and dark respiration of these microalgae was measured under culture conditions and three cell concentrations, while varying O₂ concentrations in the Oroboros [[NextGen-O2k]] equipped with the PhotoBiology-Module [1] during stepwise increases of blue actinic light from from 10 to 350 µmol∙s^-1∙m^-2, followed by darkness, again at various controlled O₂ concentrations. Maximum net photosynthesis was inhibited by 40 % at hyperoxic O₂ concentrations of 550 to 650 µM, when ROS production is known to be increased [2,3]. Transient light-enhanced dark respiration [4] peaked within 30 to 60 s after light-dark transitions and was 3.5- to 4-fold higher than steady-state dark respiration independent of O₂ concentration in the range of 200 to 650 µM. </br></br>We conclude that high-resolution photorespiratory analysis provides a new method to investigate the oxygen kinetics of O₂ production and O₂ consumption that reveal interactions of chloroplasts and mitochondria under precisely regulated experimental light and oxygen regimes.</br><small></br># Went N, Di Marcello M, Gnaiger E (2021) Oxygen dependence of photosynthesis and light-enhanced dark respiration studied by High-Resolution PhotoRespirometry. https://doi.org/10.26124/mitofit:2021-0005</br># Komlódi T, Sobotka O, Gnaiger E (2021) Facts and artefacts on the oxygen dependence of hydrogen peroxide production using Amplex UltraRed. https://doi.org/10.26124/bec:2021-0004</br># Shimakawa G, Kohara A, Miyake C (2020) Characterization of light-enhanced respiration in cyanobacteria. https://doi.org/10.3390/ijms22010342</br></small>drogen peroxide production using Amplex UltraRed. https://doi.org/10.26124/bec:2021-0004 # Shimakawa G, Kohara A, Miyake C (2020) Characterization of light-enhanced respiration in cyanobacteria. https://doi.org/10.3390/ijms22010342 </small>)
• Gerisch 2020 Dev Cell  + (All animals have evolved the ability to su … All animals have evolved the ability to survive nutrient deprivation, and nutrient signaling pathways are conserved modulators of health and disease. In ''C. elegans'', late-larval starvation provokes the adult reproductive diapause (ARD), a long-lived quiescent state that enables survival for months without food, yet underlying molecular mechanisms remain unknown. Here, we show that ARD is distinct from other forms of diapause, showing little requirement for canonical longevity pathways, autophagy, and fat metabolism. Instead it requires the HLH-30/TFEB transcription factor to promote the morphological and physiological remodeling involved in ARD entry, survival, and recovery, suggesting that HLH-30 is a master regulator of reproductive quiescence. HLH-30 transcriptome and genetic analyses reveal that Max-like HLH factors, AMP-kinase, mTOR, protein synthesis, and mitochondrial fusion are target processes that promote ARD longevity. ARD thus rewires metabolism to ensure long-term survival and may illuminate similar mechanisms acting in stem cell quiescence and long-term fasting.</br></br><small>Copyright © 2020 Elsevier Inc. All rights reserved.</small> 2020 Elsevier Inc. All rights reserved.</small>)
• Hernansanz-Agustin 2019 bioRxiv  + (All metazoans depend on O<sub>2</ … All metazoans depend on O₂ delivery and consumption by the mitochondrial oxidative phosphorylation (OXPHOS) system to produce energy. A decrease in O₂ availability (hypoxia) leads to profound metabolic rewiring. In addition, OXPHOS uses O₂ to produce reactive oxygen species (ROS) that can drive cell adaptations through redox signalling, but also trigger cell damage, and both phenomena occur in hypoxia. However, the precise mechanism by which acute hypoxia triggers mitochondrial ROS production is still unknown. Ca²⁺ is one of the best known examples of an ion acting as a second messenger, yet the role ascribed to Na⁺ is to serve as a mere mediator of membrane potential and collaborating in ion transport. Here we show that Na⁺ acts as a second messenger regulating OXPHOS function and ROS production by modulating fluidity of the inner mitochondrial membrane (IMM). We found that a conformational shift in mitochondrial complex I during acute hypoxia drives the acidification of the matrix and solubilization of calcium phosphate precipitates. The concomitant increase in matrix free-Ca²⁺ activates the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX), which imports Na⁺ into the matrix. Na⁺ interacts with phospholipids reducing IMM fluidity and mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III, generating a redox signal. Inhibition of mitochondrial Na⁺ import through NCLX is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na⁺ import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolismlt;/sup> import into the mitochondrial matrix controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences in cellular metabolism)
• Hernansanz-Agustin 2020 Nature  + (All metazoans depend on the consumption of … All metazoans depend on the consumption of O₂ by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O₂ to produce reactive oxygen species that can drive cell adaptations, a phenomenon that occurs in hypoxia and whose precise mechanism remains unknown. Ca²⁺ is the best known ion that acts as a second messenger, yet the role ascribed to Na⁺ is to serve as a mere mediator of membrane potential. Here we show that Na⁺ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia drives acidification of the matrix and the release of free Ca²⁺ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na⁺/Ca²⁺ exchanger promotes the import of Na⁺ into the matrix. Na⁺ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na⁺ import through the Na⁺/Ca²⁺ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na⁺ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.oxia. These results reveal that Na⁺ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.)
• Neves 2015 Elife  + (All organisms live within a given thermal … All organisms live within a given thermal range, but little is known about the mechanisms setting the limits of this range. We uncovered cellular features exhibiting signature changes at thermal limits in ''Caenorhabditis elegans'' embryos. These included changes in embryo size and shape, which were also observed in ''Caenorhabditis briggsae'', indicating evolutionary conservation. We hypothesized that such changes could reflect restricted aerobic capacity at thermal limits. Accordingly, we uncovered that relative respiration in ''C. elegans'' embryos decreases at the thermal limits as compared to within the thermal range. Furthermore, by compromising components of the respiratory chain, we demonstrated that the reliance on aerobic metabolism is reduced at thermal limits. Moreover, embryos thus compromised exhibited signature changes in size and shape already within the thermal range. We conclude that restricted aerobic metabolism at the thermal limits contributes to setting the thermal range in a metazoan organism. the thermal range in a metazoan organism.)
• Wilmshurst 1998 BMJ  + (All organisms require oxygen for metabolis … All organisms require oxygen for metabolism, but the oxygen in water is unavailable to mammals. Divers (and diving mammals such as whales and seals) are entirely dependent on the oxygen carried in the air in their lungs or their gas supply. Divers also have a paradoxical problem with oxygen. At higher partial pressures oxygen causes acute toxicity leading to convulsions. To understand the diver's narrow knife edge between fatal hypoxia and fatal hyperoxia we need to recall some of the physical properties of gases. At sea level atmospheric pressure is 1 bar absolute (1 standard atmosphere =101 kPa=1.013 bars). The weight of the atmosphere exerts a pressure which will support a column of water 10 m high; 10 m under water the pressure on a diver is 200 kPa. The volume of gas in an early diving bell full of air at sea level is halved at 10 m according to Boyle's law; at 20 m pressure is 300 kPa absolute and the gas is compressed into one third the volume. Dry air is composed of roughly 21 % oxygen, 78 % nitrogen, and 1 % other gases. According to Dalton's law the partial pressure of oxygen at any depth will be 21 % of the total pressure exerted by the air and the partial pressure of nitrogen will be 78 % of total pressure. Gases dissolve in the liquid with which they are in contact. Nitrogen is fat soluble and at sea level we have several litres dissolved in our bodies. If the partial pressure of nitrogen is doubled (by breathing air at 10  m depth) for long enough for equilibration to take place we will contain twice as many dissolved nitrogen molecules as at sea level. Gases dissolve in the liquid with which they are in contact. Nitrogen is fat soluble and at sea level we have several litres dissolved in our bodies. If the partial pressure of nitrogen is doubled (by breathing air at 10  m depth) for long enough for equilibration to take place we will contain twice as many dissolved nitrogen molecules as at sea level. The effect of the increased partial pressures of oxygen is more complex. Doubling our inspired partial pressure of oxygen doubles the amount of oxygen in solution but does not double the amount of oxygen in the body since a large part of our oxygen content is bound to oxygen carrying pigments. The haemoglobin in arterial blood is virtually saturated at an inspired partial pressure of oxygen (Fio2) of 21 kPa, and increasing the partial pressure of oxygen has little effect on the amount of oxygen bound to haemoglobin.the amount of oxygen bound to haemoglobin.)
• Silvia 1976 American Psychological Association  + (All students and professors need to write, … All students and professors need to write, and many struggle to finish their stalled dissertations, journal articles, book chapters, or grant proposals. Writing is hard work and can be difficult to wedge into a frenetic academic schedule.</br></br>In this practical, light-hearted, and encouraging book, Paul Silvia explains that writing productively does not require innate skills or special traits but specific tactics and actions. Drawing examples from his own field of psychology, he shows readers how to overcome motivational roadblocks and become prolific without sacrificing evenings, weekends, and vacations. After describing strategies for writing productively, the author gives detailed advice from the trenches on how to write, submit, revise, and resubmit articles, how to improve writing quality, and how to write and publish academic work.nd how to write and publish academic work.)
• Cubizolle 2020 J Cell Mol Med  + (All-trans-retinal (atRAL) is a highly reac … All-trans-retinal (atRAL) is a highly reactive carbonyl specie, known for its reactivity on cellular phosphatidylethanolamine in photoreceptor. It is generated by photoisomerization of 11-cis-retinal chromophore linked to opsin by the Schiff's base reaction. In ABCA4-associated autosomal recessive Stargardt macular dystrophy, atRAL results in carbonyl and oxidative stress, which leads to bisretinoid A2E, accumulation in the retinal pigment epithelium (RPE). This A2E-accumulation presents as lipofuscin fluorescent pigment, and its photooxidation causes subsequent damage. Here we describe protection against a lethal dose of atRAL in both photoreceptors and RPE in primary cultures by a lipidic polyphenol derivative, an isopropyl-phloroglucinol linked to DHA, referred to as IP-DHA. Next, we addressed the cellular and molecular defence mechanisms in commonly used human ARPE-19 cells. We determined that both polyunsaturated fatty acid and isopropyl substituents bond to phloroglucinol are essential to confer the highest protection. IP-DHA responds rapidly against the toxicity of atRAL and its protective effect persists. This healthy effect of IP-DHA applies to the mitochondrial respiration. IP-DHA also rescues RPE cells subjected to the toxic effects of A2E after blue light exposure. Together, our findings suggest that the beneficial role of IP-DHA in retinal cells involves both anti-carbonyl and anti-oxidative capacities.</br></br><small>© 2020 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</small>ndation for Cellular and Molecular Medicine.</small>)
• Qi 2017 Ann Allergy Asthma Immunol  + (Allergic rhinitis is the most common of th … Allergic rhinitis is the most common of the atopic diseases, affecting up to 25% of the population worldwide. Grass pollen sensitization has been recognized as a major cause of allergic rhinitis. On the pathophysiologic level, allergic rhinitis is an IgE-mediated inflammation of the nasal mucosa. Grass pollen allergy, commonly called hay fever, can also cause more general symptoms, such as fatigue and unwellness as seen in flulike syndromes. This might be partly related to the activation of a systemic inflammatory pathway after the local nasal inflammatory response, but data from studies concerning the systemic effects of nasal mucosal allergen exposure are limited.</br></br>...ucosal allergen exposure are limited. ...)
• Mutschler 2013  + (Allergien, Burn-out, Fibromyalgie, Multipl … Allergien, Burn-out, Fibromyalgie, Multiple Chemikalien-Sensitivität, Fatigue-Syndrom, … die Liste der Krankheiten, die die herkömmliche Medizin – vor allem für Kassenpatienten – weder gut diagnostizieren noch wirklich erfolgreich behandeln kann, ist lang. Hinzu kommt, dass zu den bereits Genannten fast unbegrenzt weitere Erkrankungen hinzugefügt werden müssen, von denen die Lehrmedizin meint, dass sie sie behandeln kann, ihre Behandlung dem Patienten jedoch oft auch erheblich schadet: Herz-Kreislauf-Erkrankungen, Krebs, Autoimmunerkrankungen, neurodegenerative Erkrankungen, Depressionen und viele mehr. </br>Diese Patienten werden mit einer Reihe von Pharmaka versorgt, die die Symptome der Erkrankung abmildert oder bestenfalls zum Verschwinden bringt, jedoch wird dieser „Erfolg“ mit erheblichen Nebenwirkungen teuer erkauft. Meist ist die jahrzehntelange „Patienten-Karriere“ bereits klar vorgezeichnet, wenn ein Mensch in die Mühle der pharmazeutisch geprägten Medizin gerät. Es ist nur eine Frage der Zeit, wann die nächsten schwerwiegenden Symptome auftreten. Denn viele der millionenfach verschriebenen Arzneien greifen in die Physiologie einer jeden Körperzelle ein und können Stoffwechselwege ausbremsen oder gar Schäden an Organellen erzeugen – allem voran Schäden an den Mitochondrien (sekundäre Mitochondriopathien), den existenziellen Zellbestandteilen für die Energieversorgung in der kleinesten Einheit eines jeden Organs und Gewebes. Ganz zu schweigen davon, dass die ursächlich auslösenden physiologischen Bedingungen weder erkannt noch behoben werden, damit unterschwellig fortbestehen und langfristig folgerichtig weitere, neue Symptome und Erkrankungen zum Vorschein bringen. </br>Wie viel besser steht bei einem Vergleich doch die mitochondriale Medizin mit einer klar definierten Ausrichtung auf die Unterstützung und Förderung der Zellphysiologie da! Sie setzt darauf,</br>die tatsächlichen Belastungen des Körpers und seiner Zellen aufzuspüren und weitestmöglich zu beseitigen,</br>Mängel im Stoffwechsel zu orten und durch eine für den Patienten passende Ernährung und die gezielte Gabe von Makro- und Mikroelementen</br>sowie weiteren Vitalstoffen aufzuheben sowie durch geeignete Maßnahmen die Regeneration und die Teilung der Mitochondrien anzuregen und den gesamten Zellstoffwechsel zu unterstützen und zu fördern.</br>So kann mit der Zeit wieder Gesundheit entstehen und tatsächliche Heilung ist möglich.ehen und tatsächliche Heilung ist möglich.)
• Kovalev 2018 EMBS  + (Allometric decline of mass-specific metabo … Allometric decline of mass-specific metabolic rate with increasing body size in organisms is a long-known and well-documented phenomenon. The patterns observed at the organismal level indicate fundamental allometric changes in the rate of cellular metabolism and mitochondrial functioning; however, the mechanistic causes of these differences remain under debate. The aerobic metabolic rate is performed through the mitochondrial pathway of oxidative phosphorylation. Therefore, it is meaningful to predict that allometric pattern for mitochondrial functioning would reflect the pattern of aerobic metabolism. Surprisingly, there have been relatively few studies that have assessed the possible link between mitochondrial respiration and body size in invertebrates. We studied body size dependence of mitochondrial respiration of blue mussels ''Mytilus edulis'' L. Mussels were of the same age (3 years), but differed in size. In order to test functional capacities of mitochondria from mussels of different sizes respiration was determined at normal (15°C) and elevated (27°C) exposure temperatures. Mitochondria were isolated from hepatopancreas and respiration rate was measured using high-resolution respirometry method (by Oxygraph-2k, Oroboros Instruments). Substrates, inhibitors and uncoupling agents for oxidative phosphorylation (OXPHOS) and electron transport system (ETS) were added step-by-step in order to assess maximal respiration rates, respiratory control ratio, proton leak, activity and impact of all complexes of ETC. Temperature significantly accelerated state 3 (ADP-stimulated) mitochondrial respiration, maximal respiration with uncoupled ETS, and caused an increase of Respiratory Control Ratios. On the contrary, state 4 respiration (indicative of the proton leak) as well as respiration related to electron flux through complexes of ETC did not show an increase at stress temperature (27°C). Body size of mussels had a strong effect on most studied parameters. ADP-stimulated respiration, electron flux through complex IV, proton leak and uncoupled respiration showed a pronounced increase with body mass of mussels with power coefficients of 1.8, 1.2, 0.2 and 0.8, respectively. The obtained results showed that larger mussels had higher OXPHOS rates than smaller ones. Since all mussels were of the same age, larger ones obviously were characterized by rapid growth. It is possible that elevated growth abilities in some specimens compared to the others result from more efficient metabolic regulation which in turn is related to higher mitochondrial capacities.elated to higher mitochondrial capacities.)
• Miettinen 2017 Trends Cell Biol  + (Allometric scaling of metabolic rate resul … Allometric scaling of metabolic rate results in lower total mitochondrial oxygen consumption with increasing organismal size. This is considered a universal law in biology. Here, we discuss how allometric laws impose size-dependent limits to mitochondrial activity at the cellular level. This cell-size-dependent mitochondrial metabolic activity results in nonlinear scaling of metabolism in proliferating cells, which can explain size homeostasis. The allometry in mitochondrial activity can be controlled through mitochondrial fusion and fission machinery, suggesting that mitochondrial connectivity can bypass transport limitations, the presumed biophysical basis for allometry. As physical size affects cellular functionality, cell-size-dependent metabolism becomes directly relevant for development, metabolic diseases, and aging.evelopment, metabolic diseases, and aging.)
• Nold 2019 Psychoneuroendocrinology  + (Allostasis is the process by which the bod … Allostasis is the process by which the body’s physiological systems adapt to environmental changes. Chronic stress increases the allostatic load to the body, producing wear and tear that could, over time, become pathological. In this study, young adult male Wistar Kyoto rats were exposed to an unpredictable chronic mild stress (uCMS) protocol to increase allostatic load. First, physiological systems which may be affected by extended uCMS exposure were assessed. Secondly, 5 weeks of uCMS were used to investigate early adaptations in the previously selected systems. Adverse experiences during developmentally sensitive periods like adolescence are known to severely alter the individual stress vulnerability with long-lasting effects. To elucidate how early life adversity impacts stress reactivity in adulthood, an additional group with juvenile single-housing (JSH) prior to uCMS was included in the second cohort. The aim of this work was to assess the impact of chronic stress with or without adversity during adolescence on two domains known to be impacted in numerous stress-related disorders: mitochondrial energy metabolism and the immune system. Both, uCMS and adolescence stress increased kynurenine and kynurenic acid in plasma, suggesting a protective, anti-oxidant response from the kynurenine pathway. Furthermore, uCMS resulted in a down-regulation of immediate early gene expression in the prefrontal cortex and hippocampus, while only rats with the double-hit of adolescent stress and uCMS demonstrated increased mitochondrial activity in the hippocampus. These results suggest that early life adversity may impact on allostatic load by increasing energetic requirements in the brain.asing energetic requirements in the brain.)
• Opperdoes 2024 BMC Genomics  + (Almost all extant organisms use the same, … Almost all extant organisms use the same, so-called canonical, genetic code with departures from it being very rare. Even more exceptional are the instances when a eukaryote with non-canonical code can be easily cultivated and has its whole genome and transcriptome sequenced. This is the case of ''Blastocrithidia nonstop'', a trypanosomatid flagellate that reassigned all three stop codons to encode amino acids.</br></br>We ''in silico'' predicted the metabolism of ''B. nonstop'' and compared it with that of the well-studied human parasites ''Trypanosoma brucei'' and ''Leishmania major''. The mapped mitochondrial, glycosomal and cytosolic metabolism contains all typical features of these diverse and important parasites. We also provided experimental validation for some of the predicted observations, concerning, specifically presence of glycosomes, cellular respiration, and assembly of the respiratory complexes.</br></br>In an unusual comparison of metabolism between a parasitic protist with a massively altered genetic code and its close relatives that rely on a canonical code we showed that the dramatic differences on the level of nucleic acids do not seem to be reflected in the metabolisms. Moreover, although the genome of ''B. nonstop'' is extremely AT-rich, we could not find any alterations of its pyrimidine synthesis pathway when compared to other trypanosomatids. Hence, we conclude that the dramatic alteration of the genetic code of ''B. nonstop'' has no significant repercussions on the metabolism of this flagellate.ions on the metabolism of this flagellate.)
• Zhu 2019 Aging Cell  + (Alogliptin is a commonly prescribed drug t … Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long-term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high-fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.</br></br><small>© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.</small>mical Society and John Wiley & Sons Ltd.</small>)
• Dieter 2022 Int J Mol Sci  + (Alpha lipoic acid (ALA) is a sulphur-conta … Alpha lipoic acid (ALA) is a sulphur-containing organic compound, derived from octanoic acid, and an important cofactor for mitochondrial respiratory enzymes. It has strong antioxidant properties that improve mitochondrial function. We investigated if ALA improves mitochondrial dysfunction in a cellular model of Alzheimer's disease (AD).</br></br>SH-SY5Y-APP₆₉₅ cells were used as a model for an early stage of AD. Vector-transfected SH-SY5Y-MOCK cells served as controls. Using these cells, we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, and citrate synthase activity (CS) in cells treated with ALA. Cells were treated for 24 h with different concentrations of ALA and with or without the complex I inhibitor rotenone.</br></br>Incubation with ALA showed a significant increase in ATP levels in both SH-SY5Y-APP₆₉₅ and SH-SY5Y-MOCK cells. MMP levels were elevated in SH-SY5Y-MOCK cells, treatment with rotenone showed a reduction in MMP, which could be partly alleviated after incubation with ALA in SH-SY5Y-MOCK cells. ALA treatment showed significant differences in respiration chain complex activities in SH-SY5Y-MOCK cells. Citrate synthase activity was unaffected. ROS levels were significantly lower in both cell lines treated with ALA.</br></br>ALA increased the activity of the different complexes of the respiratory chain, and consequently enhanced the MMP, leading to increased ATP levels indicating improved mitochondrial function. ALA only marginally protects from additional rotenone-induced mitochondrial stress.ly protects from additional rotenone-induced mitochondrial stress.)
• Tretter 2005 Philos Trans R Soc Lond B Biol Sci  + (Alpha-ketoglutarate dehydrogenase (alpha-K … Alpha-ketoglutarate dehydrogenase (alpha-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of alpha-ketoglutarate to succinyl-CoA and produces NADH directly providing electrons for the respiratory chain. alpha-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than alpha-KGDH to ROS but as long as alpha-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when alpha-KGDH is also inhibited by ROS. In addition being a key target, alpha-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD+ ratio. The pathological relevance of these two features of alpha-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.ic for several neurodegenerative diseases.)
• Dohlmann 2013 Abstract IOC75  + (Alteration in mitochondrial respiratory ca … Alteration in mitochondrial respiratory capacity has been linked to several conditions that are associated with a sedentary lifestyle, such as obesity and insulin resistance. </br>It is well known that endurance training can diminish these conditions, but some high intensity interval training (HIIT) protocols have shown similar improvements in insulin sensitivity, in spite of the reduced training volume. However it is sparse with literature regarding HIIT and the effect on mitochondrial respiratory capacity. </br>The aim of this study was to investigate the effects of a low volume HIIT protocol on mitochondrial respiratory capacity and VO2max in sedentary overweight adults. </br>8 healthy sedentary men (n=2) and women (n=6) (age 40±3 yrs, BMI 32±2, VO2max 2383 ±115 ml•min-1) were recruited for this study. They underwent 6 weeks of supervised HIIT on a cycle ergometer (18 sessions of 7x1min exercise bouts interspersed with 1min rest periods). Muscle biopsies were taken from m. vastus lateralis before and after training. Mitochondrial respiratory capacity was measured ex vivo in permeabilized muscle fibers using high resolution respirometry (Oxygraph-2k, Oroboros, Innsbruck, Austria). The respiratory protocol investigated maximal coupled state 3 respiration (complex I + II linked substrates) with the following substrates (malate, glutamate, octanoyl carnitine, succinate and ADP; GMSO3), as well as state 4o (oligomycin; LEAK). Body composition was measured by DXA, and VO2max using an incremental cycle test to exhaustion. Mitochondrial respiratory capacity increased significantly following training; GMSO3 respiration increased by 13% (57± 4 to 64±5 pmol O2•mg-1•s-1) and LEAK respiration increased by 24% (21±2 to 25±2 pmol O2 •mg-1•s-1).The present training protocol didn’t elicit a significant improvement in VO2max (4%, P = 0.37), but time to fatigue during the VO2max test was significantly increased by 18% post training (P <0.001). BMI and body composition were not changed following training.</br>Interestingly the present training protocol induced a significant improvement in mitochondrial respiratory capacity, but not in whole body VO2max, thus implying that the training stimulus was adequate to improve the respiratory capacity locally. The observed improvement in mitochondrial respiratory capacity and time to fatigue suggest that the HIIT training may induce positive metabolic effects that can attenuate the development of lifestyle diseases, independently of VO2max.</br></br>The project is funded by the EU FP7 program The project is funded by the EU FP7 program)
• Rigoni 2016 Abstract Mito Xmas Meeting Innsbruck  + (Alteration of mitochondrial ultrastructure … Alteration of mitochondrial ultrastructure has emerged as phenotypical marker of dysfunction. In particular, changes in cristae shape and number regulate the respiratory efficiency of the cell and the release of proapoptotic factors. Moreover, in the last years a growing number of studies have observed a loss of mtDNA associated to mitochondrial related disorders but whether and how mtDNA and nucleoids regulation is influenced by mitochondrial ultrastructure is unknown. To address this question we studied nucleoids distribution and mtDNA copynumber in cellular models where the mitochondrial ultrastructure has been altered. We show that nucleoids distribution vary depending on mitochondrial ultrastructure and accordingly also mtDNA copy number. Furthermore, we have identified a mitochondrial complex that decrease with nucleoids suggesting a relevant role of this complex for nucleoids and mtDNA stability. Our results suggest that nucleoids and mtDNA stability is regulated by mitochondrial ultrastructure.regulated by mitochondrial ultrastructure.)
• Schneeberger 2015 Cell Rep  + (Alterations in ER homeostasis have been im … Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D.contributor to the pathophysiology of T2D.)
• Beaudoin 2014 J Physiol  + (Alterations in lipid metabolism within the … Alterations in lipid metabolism within the heart may have a causal role in the establishment of diabetic cardiomyopathy, however this remains equivocal. Therefore, in the current study we determined cardiac mitochondrial bioenergetics in ZDF rats before overt type 2 diabetes and diabetic cardiomyopathy developed. In addition, we utilized resveratrol, a compound previously shown to improve prevent or reverse cardiac dysfunction in high fat-fed rodents, as a tool to potential recover dysfunctions within mitochondria. Fasting blood glucose and invasive left ventricular hemodynamic analysis confirmed the absence of type 2 diabetes and diabetic cardiomyopathy. However, fibrosis was already increased (P<0.05) ~70% in ZDF rats at this early stage in disease progression. Assessments of mitochondrial ADP and pyruvate respiratory kinetics in permeabilized fibres from the left ventricle revealed normal electron transport chain function and content. In contrast, the apparent Km to palmitoyl-CoA (P-CoA) was increased (P<0.05) ~60%, which was associated with an accumulation of intracellular triacylgycerol, diacylglycerol and ceramide species. In addition, the capacity for mitochondrial ROS emission was increased (P<0.05) ~3-fold in ZDF rats. The provision of resveratrol recovered fibrosis, P-CoA respiratory sensitivity, reactive lipid accumulation and mitochondrial reactive oxygen species emission rates. Altogether the current data supports the supposition that a chronic dysfunction within mitochondrial lipid-supported bioenergetics contributes to the development of diabetic cardiomyopathy, as this was present before overt diabetes or cardiac dysfunction. In addition, we show resveratrol supplementation prevents these changes, supporting the belief that resveratrol is a potent therapeutic approach for preventing diabetic cardiomyopathy.ic approach for preventing diabetic cardiomyopathy.)
• Lores-Arnaiz 2016 Neurochem Res  + (Alterations in mitochondrial bioenergetics … Alterations in mitochondrial bioenergetics have been associated with brain aging. In order to evaluate the susceptibility of brain cortex synaptosomes and non-synaptic mitochondria to aging-dependent dysfunction, male Swiss mice of 3 or 17 months old were used. Mitochondrial function was evaluated by oxygen consumption, mitochondrial membrane potential and respiratory complexes activity, together with UCP-2 protein expression. Basal respiration and respiration driving proton LEAK were decreased by 26 and 33 % in synaptosomes from 17-months old mice, but spare respiratory capacity was not modified by aging. Succinate supported state 3 respiratory rate was decreased by 45 % in brain cortex non-synaptic mitochondria from 17-month-old mice, as compared with young animals, but respiratory control was not affected. Synaptosomal mitochondria would be susceptible to undergo calcium-induced depolarization in 17 months-old mice, while non-synaptic mitochondria would not be affected by calcium overload. UCP-2 was significantly up-regulated in both synaptosomal and submitochondrial membranes from 17-months old mice, compared to young animals. UCP-2 upregulation seems to be a possible mechanism by which mitochondria would be resistant to suffer oxidative damage during aging.t to suffer oxidative damage during aging.)
• Fahlbusch 2022 Int J Mol Sci  + (Alterations in mitochondrial function are … Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD.served in the early stages of human MAFLD.)