Westerlund 2024 Heliyon
| Westerlund E, Marelsson SE, Karlsson M, Sjövall F, Chamkha I, Åsander Frostner E, Lundgren J, Fellman V, Eklund EA, Steding-Ehrenborg K, Darin N, Paul G, Hansson MJ, Ehinger JK, Elmér E (2024) Correlation of mitochondrial respiration in platelets, peripheral blood mononuclear cells and muscle fibers. Heliyon 10:e26745. https://doi.org/10.1016/j.heliyon.2024.e26745 |
Westerlund Emil, Marelsson SE, Karlsson M, Sjoevall Frederik, Chamkha I, Aasander-Frostner Eleonor, Lundgren Johan, Fellman Vineta, Eklund Erik A, Steding-Ehrenborg K, Darin Niklas, Paul Gesine, Hansson Magnus J, Ehinger Johannes K, Elmer Eskil (2024) Heliyon
Abstract: There is a growing interest for the possibility of using peripheral blood cells (including platelets) as markers for mitochondrial function in less accessible tissues. Only a few studies have examined the correlation between respiration in blood and muscle tissue, with small sample sizes and conflicting results. This study investigated the correlation of mitochondrial respiration within and across tissues. Additional analyses were performed to elucidate which blood cell type would be most useful for assessing systemic mitochondrial function. There was a significant but weak within tissue correlation between platelets and peripheral blood mononuclear cells (PBMCs). Neither PBMCs nor platelet respiration correlated significantly with muscle respiration. Muscle fibers from a group of athletes had higher mass-specific respiration, due to higher mitochondrial content than non-athlete controls, but this finding was not replicated in either of the blood cell types. In a group of patients with primary mitochondrial diseases, there were significant differences in blood cell respiration compared to healthy controls, particularly in platelets. Platelet respiration generally correlated better with the citrate synthase activity of each sample, in comparison to PBMCs. In conclusion, this study does not support the theory that blood cells can be used as accurate biomarkers to detect minor alterations in muscle respiration. However, in some instances, pronounced mitochondrial abnormalities might be reflected across tissues and detectable in blood cells, with more promising findings for platelets than PBMCs.
• Bioblast editor: Gnaiger E • O2k-Network Lab: SE Lund Elmer E
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style, mt-Medicine
Stress:Mitochondrial disease Organism: Human Tissue;cell: Skeletal muscle, Blood cells, Platelet Preparation: Permeabilized cells, Permeabilized tissue, Intact cells Enzyme: Marker enzyme, TCA cycle and matrix dehydrogenases Regulation: Coupling efficiency;uncoupling Coupling state: ET, LEAK, ROUTINE, OXPHOS Pathway: N, S, CIV, NS, ROX HRR: Oxygraph-2k
PBMC
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, Søndergaard H, Munch-Andersen T, Damsgaard R, Hagen C, Díez-Sánchez 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, Méndez 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
