Sjoevall 2014 PLoS One
SjΓΆvall F, Morota S, Asander Frostner E, Hansson Magnus J, Elmer E (2014) Cytokine and nitric oxide levels in patients with sepsis - temporal evolvement and relation to platelet mitochondrial respiratory function. PLoS One 9:e97673. |
Sjoevall F, Morota S, Asander Frostner E, Hansson Magnus J, Elmer E (2014) PLoS One
Abstract: The levels of nitric oxide (NO) and various cytokines are known to be increased during sepsis. These signaling molecules could potentially act as regulators and underlie the enhancement of mitochondrial function described in the later phase of sepsis. Therefore, we investigated the correlation between observed changes in platelet mitochondrial respiration and a set of pro- and anti-inflammatory cytokines as well as NO plasma levels in patients with sepsis.
Platelet mitochondrial respiration and levels of TNFΞ±, MCP-1 (monocyte chemotactic protein-1), INFΞ³ (interferon-Ξ³), IL-1Ξ², IL-4, IL-5, IL-6, IL-8, IL-10 and IL-17 and NO were analyzed in 38 patients with severe sepsis or septic shock at three time points during one week following admission to the ICU. Citrate synthase, mitochondrial DNA and cytochrome c were measured as markers of cellular mitochondrial content. All mitochondrial respiratory states increased over the week analyzed (p<0.001). IL-8 levels correlated with maximal mitochondrial respiration on day 6-7 (p = 0.02, r2 = 0.22) and was also higher in non-survivors compared to survivors on day 3-4 and day 6-7 (p = 0.03 respectively). Neither NO nor any of the other cytokines measured correlated with respiration or mortality. Cytochrome c levels were decreased at day 1-2 by 24Β±5% (p = 0.03) and returned towards values of the controls at the last two time points. Citrate synthase activity and mitochondrial DNA levels were similar to controls and remained constant throughout the week.
Out of ten analyzed cytokines and nitric oxide, IL-8 correlated with the observed increase in mitochondrial respiration. This suggests that cytokines as well as NO do not play a prominent role in the regulation of platelet mitochondrial respiration in sepsis. Further, the respiratory increase was not accompanied by an increase in markers of mitochondrial content, suggesting a possible role for post-translational enhancement of mitochondrial respiration rather than augmented mitochondrial mass.
β’ O2k-Network Lab: SE Lund Elmer E
Coupling control and the Q-junction
- Mitochondrial coupling control states are measured without simultaneous change of a selected pathway control state, i.e. coupling control is separated from pathway control. Biochemical coupling efficiencies (E-L coupling efficiencies) and P-L coupling efficiencies are, therefore, studied at a defined pathway control state that must not change between measurement of LEAK respiration L, OXPHOS capacity P, and electron transfer capacity E.
- A physiologically relevant pathway control state for partial reconstitution of TCA cycle function is obtained by supply of NADH-linked substrates (e.g. pyruvate&malate PM; N-pathway) in combination with succinate (S; S-pathway), supporting convergent electron transfer through Complexes I and II into the Q-junction (NS-pathway). OXPHOS- and ET-capacities are higher in the combined NS-pathway than in the separate N- or S-pathway (Gnaiger 2020). Is the NS-pathway control state appropriate for the analysis of coupling control?
- Partial additivity in OXPHOS capacity NSP or ET capacity NSE implies that there is competition between the N- and S-pathway, when the NS-pathway capacity is less than the arithmetic sum of the constituent pathway capacities. In mitochondria with lower OXPHOS than ET capacity (P<E; when the phosphorylation system is limiting), the competition in NSE is increasingly pronounced in NSP, and when respiration is further reduced by complete inhibition of the phosphorylation system (e.g. by oligomycin), competition between the N- and S-pathways is maximal in LEAK respiration. Different levels of competition imply that the ratio of the effective N- and S-pathway in the NS-pathway state may shift to the extent that the dominant pathway may fully outcompete the other in the LEAK state. Convergent electron input into the Q-junction in NSE, therefore, may shift to single electron input through either the dominant N- or S-pathway in NSL, which then would effectively correspond to either NL or SL. This has deep implications on LEAK respiration, since the N-pathway has three coupling sites (H+ pumps: CI, CIII, CIV) with a correspondingly higher H+/O2 ratio compared to the S-pathway with two coupling sites (H+ pumps: CIII, CIV). A higher rate of the proton leak is implied when measuring the same rate of LEAK respiration in NL than when observing an identical oxygen consumption rate in SL.
- When inhibiting O2 consumption by oligomycin in the NS-pathway state, the relative contribution of the N- and S-pathways to LEAK respiration is not known. By subsequent uncoupler titrations, the relative contribution of these pathways is likely to change, thus obtaining an undefined combination of pathway control and coupling control. In conclusion, the NS-pathway state is not appropriate for studying coupling control. Coupling control is best studied in the separate N- or S-pathway (Gnaiger et al 2000; 2015).
- Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. Bioenerg Commun 2020.2. https://doi.org/10.26124/bec:2020-0002
- Gnaiger E, Boushel R, SΓΈndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, DΓez-SΓ‘nchez C, Ara I, Wright-Paradis C, Schrauwen P, Hesselink M, Calbet JAL, Christiansen M, Helge JW, Saltin B (2015) Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and caucasians in the arctic winter. https://doi.org/10.1111/sms.12612
- Gnaiger E, MΓ©ndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci U S A 97:11080-5. https://doi.org/10.1073/pnas.97.20.11080
Labels: MiParea: Respiration, mt-Medicine, Patients Pathology: Sepsis
Organism: Human Tissue;cell: Blood cells, Platelet Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ET
Pathway: N, S, CIV, NS, ROX
HRR: Oxygraph-2k
JP, SE, MitoEAGLE blood cells data, MitoFit 2021 PLT