Sjoevall 2013 Crit Care

From Bioblast
Publications in the MiPMap
Sjoevall F, Morota S, Persson J, Hansson Magnus J, Elmer E (2013) Patients with sepsis exhibit increased mitochondrial respiratory capacity in peripheral blood immune cells. Crit Care 17:R152.

Β» PMID: 23883738 Open Access

Sjoevall F, Morota S, Persson J, Hansson Magnus J, Elmer E (2013) Crit Care

Abstract: INTRODUCTION: In sepsis, mitochondria have been associated with both initial dysfunction and subsequent upregulation (biogenesis). However, the evolvement of mitochondrial function in sepsis over time is largely unknown, and we therefore investigated mitochondrial respiration in peripheral blood immune cells (PBICs) in sepsis patients during the first week after admission to the intensive care unit (ICU).

METHODS: PBICs from 20 patients with severe sepsis or septic shock were analyzed with high-resolution respirometry 3 times after admission to the ICU (within 48 hours, days 3 to 4 and days 6 to 7). Mitochondrial DNA (mtDNA), cytochrome c (Cyt c), and citrate synthase (CS) were measured as indicators of cellular mitochondrial content.

RESULTS: In intact PBICs with endogenous substrates, a gradual increase in cellular respiration reached 173% of controls after 1 week (P = 0.001). In permeabilized cells, respiration using substrates of Complex I, II, and IV were significantly increased days 1 to 2, reaching 137%, 130%, and 173% of controls, respectively. In parallel, higher levels of CS activity, mtDNA, and Cyt c content in PBICs (211%, 243%, and 331% of controls for the respective indicators were found at days 6 to 7; P < 0.0001). No differences in respiratory capacities were noted between survivors and nonsurvivors at any of the time points measured.

CONCLUSIONS: PBICs from patients with sepsis displayed higher mitochondrial respiratory capacities compared with controls, due to an increased mitochondrial content, as indicated by increased mitochondrial DNA, protein content, and enzyme activity. The results argue against mitochondrial respiratory dysfunction in this type of cells in sepsis.


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).
  1. 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
  2. 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
  3. 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  Pathology: Sepsis 

Organism: Human  Tissue;cell: Blood cells  Preparation: Permeabilized cells, Intact cells 


Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k 

JP, SE, MitoEAGLE blood cells data 


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