Control of mitochondrial respiration

Tager, J. M.; Wanders, R. J. A.; Groen, Albert K.; Kunz, Wolfram S.; Bohnensack, Ralf; Küster, U; Letko, G; Böhme, G; Duszyński, Jerzy; Wojtczak, Lech

doi:10.1016/0014-5793(83)80330-5

Cited by 209 publications

(84 citation statements)

References 49 publications

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“…Chance and Williams assumed, on the basis of experiments with isolated mitochondria, that ADP formed to perform cell work represents a feedback signal, which regulates OXPHOS (1)(2)(3). This view has been supported by the inverse correlation between mitochondrial activity and extramitochondrial phosphorylation potential observed in experiments with mitochondria isolated from several tissues (4), and was also predicted by computer simulations that considered the increased ADP and P i levels to be direct activators of OXPHOS (5). However, the results of studies of intact tissues do not fit into the concept of regulation of OXPHOS simply by fluctuations in ADP and Pi (3,6,7).…”

Section: The Regulation Of Oxphosmentioning

confidence: 93%

The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

et al. 2013

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This review focuses on problems of the intracellular regulation of mitochondrial function in the brain via the (i) supply of mitochondria with ADP by means of ADP shuttles and channels and (ii) the Ca 21 control of mitochondrial substrate supply. The permeability of the mitochondrial outer membrane for adenine nucleotides is low. Therefore rate dependent concentration gradients exist between the mitochondrial intermembrane space and the cytosol. The existence of dynamic ADP gradients is an important precondition for the functioning of ADP shuttles, for example CrP-shuttle. Cr at mM concentrations instead of ADP diffuses from the cytosol through the porin pores into the intermembrane space.

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Section: The Regulation Of Oxphosmentioning

confidence: 93%

The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

et al. 2013

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“…However, according to the summation theory for flux control (34), the sum of all the control coefficients in any pathway is equal to unity; so in the case of the three complexes described above the total is 0.63. Other systems known to contribute to the control of mitochondrial respiration are; adenine translocator (43,47), phosphate carrier and calcium (48,49), proton leak (50), ADP-regenerating system and dicarboxylate carrier (43).…”

Section: Energy Thresholds In Synaptic Mitochondriamentioning

confidence: 99%

Energy Thresholds in Brain Mitochondria

Davey

Peuchen

Clark

1998

Journal of Biological Chemistry

328

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Decreases in mitochondrial respiratory chain complex activities have been implicated in neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. However, the extent to which these decreases cause a disturbance in oxidative phosphorylation and energy homeostasis in the brain is not known. We therefore examined the relative contribution of individual mitochondrial respiratory chain complexes to the control of NAD-linked substrate oxidative phosphorylation in synaptic mitochondria. Titration of complex I, III, and IV activities with specific inhibitors generated threshold curves that showed the extent to which a complex activity could be inhibited before causing impairment of mitochondrial energy metabolism. Complex I, III, and IV activities were decreased by approximately 25, 80, and 70%, respectively, before major changes in rates of oxygen consumption and ATP synthesis were observed. These results suggest that, in mitochondria of synaptic origin, complex I activity has a major control of oxidative phosphorylation, such that when a threshold of 25% inhibition is exceeded, energy metabolism is severely impaired, resulting in a reduced synthesis of ATP. Additionally, depletion of glutathione, which has been reported to be a primary event in idiopathic Parkinson's disease, eliminated the complex I threshold in PC12 cells, suggesting that antioxidant status is important in maintaining energy thresholds in mitochondria. The implications of these findings are discussed with respect to neurodegenerative disorders and energy metabolism in the synapse.

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“…The ATP synthase has been proposed to be regulated by inhibitory proteins, one of which is calcium-sensitive (Yamada & Huzel, 1988;Chernyak & Koslov, 1986;Das & Harris, 1990). (6) Application of the concepts and methods of metabolic control theory to isolated mitochondria by Groen et al (1982) and Tager et al (1983) has led to the idea that the control over mitochondrial respiration and ATP synthesis is shared by a number of reactions and pathways, and that the distribution of control changes under different metabolic conditions. ) Glucose Fatty N Fig.…”

Section: Introductionmentioning

confidence: 99%

Control of respiration and ATP synthesis in mammalian mitochondria and cells

Brown

1992

Biochemical Journal

563

308

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We have seen that there is no simple answer to the question ‘what controls respiration?’ The answer varies with (a) the size of the system examined (mitochondria, cell or organ), (b) the conditions (rate of ATP use, level of hormonal stimulation), and (c) the particular organ examined. Of the various theories of control of respiration outlined in the introduction the ideas of Chance & Williams (1955, 1956) give the basic mechanism of how respiration is regulated. Increased ATP usage can cause increased respiration and ATP synthesis by mass action in all the main tissues. Superimposed on this basic mechanism is calcium control of matrix dehydrogenases (at least in heart and liver), and possibly also of the respiratory chain (at least in liver) and ATP synthase (at least in heart). In many tissues calcium also stimulates ATP usage directly; thus calcium may stimulate energy metabolism at (at least) four possible sites, the importance of each regulation varying with tissue. Regulation of multiple sites may occur (from a teleological point of view) because: (a) energy metabolism is branched and thus proportionate regulation of branches is required in order to maintain constant fluxes to branches (e.g. to proton leak or different ATP uses); and/or (b) control over fluxes is shared by a number of reactions, so that large increases in flux requires stimulation at multiple sites because each site has relatively little control. Control may be distributed throughout energy metabolism, possibly due to the necessity of minimizing cell protein levels (see Brown, 1991). The idea that energy metabolism is regulated by energy charge (as proposed by Atkinson, 1968, 1977) is misleading in mammals. Neither mitochondrial ATP synthesis nor cellular ATP usage is a unique function of energy charge as AMP is not a significant regulator (see for example Erecinska et al., 1977). The near-equilibrium hypothesis of Klingenberg (1961) and Erecinska & Wilson (1982) is partially correct in that oxidative phosphorylation is often close to equilibrium (apart from cytochrome oxidase) and as a consequence respiration and ATP synthesis are mainly regulated by (a) the phosphorylation potential, and (b) the NADH/NAD+ ratio. However, oxidative phosphorylation is not always close to equilibrium, at least in isolated mitochondria, and relative proximity to equilibrium does not prevent the respiratory chain, the proton leak, the ATP synthase and ANC having significant control over the fluxes. Thus in some conditions respiration rate correlates better with [ADP] than with phosphorylation potential, and may be relatively insensitive to mitochondrial NADH/NAD+ ratio.(ABSTRACT TRUNCATED AT 400 WORDS)

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Control of mitochondrial respiration

Cited by 209 publications

References 49 publications

The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

Energy Thresholds in Brain Mitochondria

Control of respiration and ATP synthesis in mammalian mitochondria and cells

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