Gnaiger 2009 Int J Biochem Cell Biol

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Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41:1837-45.

» PMID: 19467914

Gnaiger E (2009) Int J Biochem Cell Biol

Abstract:
Fig. 1. Substrate control of electron flow to oxygen through Complex I or Complex II separately (CI or CII), or simultaneously (CI&II) in mitochondrial preparations. Substrate supply restricted to pyruvate&malate, PM, or succinate&rotenone, S(Rot), exerts artificial upstream control of flux through the linear electron transport chain (ETC). With PM (or GM) as substrates, metabolite depletion (loss of citrate, isocitrate, 2-oxoglutarate and succinate from the matrix) prevents substrate supply to CII. With succinate as the only substrate, blockage of CI is necessary to prevent inhibition of succinate dehydrogenase by accumulating oxaloacetate. Combined CI&II substrate supply with simultaneous electron entry at the Q-junction exerts an additive effect on total electron flux through the convergent electron transfer system (ETS). This shifts control of flux downstream towards Complexes III and IV, and towards the phosphorylation system in oxidative phosphorylation. Convergent electron flow corresponds to the operation of the tricarboxylic acid cycle in the intact cell, generating simultaneously NADH and succinate in the matrix as substrates for CI&II. This physiological state is reconsituted in mitochondrial preparations by external CI&II substrate supply (PMS; or substituting pyruvate by glutamate, GMS or GS). Substrate entry across the inner mitochondrial membrane into the mitochondrial matrix space is shown by dotted arrows (metabolite depletion from the matrix is not shown). Full arrows indicate flow of electron pairs (single arrows) split into flow of single electrons (double arrows) (Gnaiger 2009).
Maximal ADP-stimulated mitochondrial respiration depends on convergent electron flow through Complexes I&II to the Q-junction of the electron transport system (ETS). In most studies of respiratory control in mitochondrial preparations, however, respiration is limited artificially by supplying substrates for electron input through either Complex I or II. High-resolution respirometry with minimal amounts of tissue biopsy (1 to 3 mg wet weight of permeabilized muscle fibres per assay) provides a routine approach for multiple substrate-uncoupler-inhibitor titrations. Under physiological conditions, maximal respiratory capacity is obtained with glutamate&malate&succinate, reconstituting the operation of the tricarboxylic acid cycle and preventing depletion of key metabolites from the mitochondrial matrix. In human skeletal muscle, conventional assays with pyruvate&malate or glutamate&malate yield submaximal oxygen fluxes at 0.50 to 0.75 of capacity of oxidative phosphorylation (OXPHOS). Best estimates of muscular OXPHOS capacity at 37 °C [pmol O2∙s­-1∙mg-1 wet weight] with isolated mitochondria or permeabilized fibres, suggest a range of 100 to 150 and up to 180 in healthy humans with normal body mass index and top endurance athletes, but reduction to 60 to 120 in overweight healthy adults with predominantly sedentary life style. The apparent ETS excess capacity (noncoupled respiration) over ADP-stimulated OXPHOS capacity is high in skeletal muscle of active and sedentary humans, but absent in mouse skeletal muscle. Such differences of mitochondrial quality in skeletal muscle are unexpected and cannot be explained at present. A comparative data base of mitochondrial physiology may provide the key for understanding the functional implications of mitochondrial diversity from mouse to man, and evaluation of altered mitochondrial respiratory control patterns in health and disease.

Q-junction, Q-cycle, Pyruvate, Glutamate, Succinate, Tricarboxylic acid cycle O2k-Network Lab: AT Innsbruck Gnaiger E, AT Innsbruck OROBOROS


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Exercise physiology;nutrition;life style, mt-Medicine Mammal;model: Human, Mouse Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria Enzyme: Marker enzyme Pathology: Aging;senescence, Obesity Regulation: Coupling efficiency;uncoupling Coupling state: LEAK, OXPHOS, ETS Substrate state: CI, CII, CI&II HRR: Oxygraph-2k Additional: BMI 

Abbreviations


Further references

» MitoPedia: Respiratory states OXPHOS ROUTINE ETS LEAK  - ROX
» O2k-Publications: Human - Skeletal muscle
» O2k-Publications: Q-junction effect
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