Open-Loop Control of Oxidative Phosphorylation in Skeletal and Cardiac Muscle Mitochondria by Ca2+

Vinnakota, Kalyan C.; Singhal, Abhishek; Bergh, Françoise Van den; Bagher-Oskouei, Masoumeh; Wiseman, Robert W.; Beard, Daniel A.

doi:10.1016/j.bpj.2015.12.018

Cited by 18 publications

(24 citation statements)

References 35 publications

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“…High‐resolution respirometry determines mitochondrial function by measuring mitochondrial oxygen consumption after a bolus injection of ADP. Since the experiment is performed in a sealed chamber, all oxygen consumed after a bolus of ADP is directly related to the production of ATP through complex IV of the mitochondrial respiratory chain . While this measure is performed in non‐physiological conditions (ie, saturating O 2 ), it permits comparison of maximal aerobic function without confounding influences present in the cellular environment.…”

Section: Mitochondrial Function and Skeletal Muscle Metabolism In Metsupporting

confidence: 53%

Skeletal muscle performance in metabolic disease: Microvascular or mitochondrial limitation or both?

2018

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One of the clearly established health outcomes associated with chronic metabolic diseases (eg, type II diabetes mellitus) is that the ability of skeletal muscle to maintain contractile performance during periods of elevated metabolic demand is compromised as compared to the fatigue-resistance of muscle under normal, healthy conditions. While there has been extensive effort dedicated to determining the major factors that contribute to the compromised performance of skeletal muscle with chronic metabolic disease, the extent to which this poor outcome reflects a dysfunctional state of the microcirculation, where the delivery and distribution of metabolic substrates can be impaired, versus derangements to normal metabolic processes and mitochondrial function, versus a combination of the two, represents an area of considerable unknown. The purpose of this manuscript is to present some of the current concepts for dysfunction to both the microcirculation of skeletal muscle as well as to mitochondrial metabolism under these conditions, such that these diverse issues can be merged into an integrated framework for future investigation. Based on an interpretation of the current literature, it may be hypothesized that the primary site of dysfunction with earlier stages of metabolic disease may lie at the level of the vasculature, rather than at the level of the mitochondria. K E Y W O R D Scapillary, fatigue resistance, microcirculation, mitochondria, oxygen limitation

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Section: Mitochondrial Function and Skeletal Muscle Metabolism In Metsupporting

confidence: 53%

Skeletal muscle performance in metabolic disease: Microvascular or mitochondrial limitation or both?

2018

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“…also reported that mitochondrial NADH level was almost insensitive to Ca 2+ when pyruvate and malate were used as mitochondrial substrates (Vinnakota et al . , b ). The present simulation study is in line with these results.…”

Section: Discussionmentioning

confidence: 99%

A simulation study on the constancy of cardiac energy metabolites during workload transition

Saito

Takeuchi

Himeno

et al. 2016

The Journal of Physiology

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The cardiac energy metabolites such as ATP, phosphocreatine, ADP and NADH are kept relatively constant over a wide range of cardiac workload, though the mechanisms are not yet clarified. One possible regulator of mitochondrial metabolism is Ca , because it activates several mitochondrial enzymes and transporters. Here we constructed a mathematical model of cardiac mitochondria, including oxidative phosphorylation, substrate metabolism and ion/substrate transporters, based on experimental data, and studied whether the Ca -dependent activation mechanisms play roles in metabolite constancy. Under the in vitro condition of isolated mitochondria, where malate and glutamate were used as mitochondrial substrates, the model well reproduced the Ca and inorganic phosphate (P ) dependences of oxygen consumption, NADH level and mitochondrial membrane potential. The Ca -dependent activations of the aspartate/glutamate carrier and the F F -ATPase, and the P -dependent activation of Complex III were key factors in reproducing the experimental data. When the mitochondrial model was implemented in a simple cardiac cell model, simulation of workload transition revealed that cytoplasmic Ca concentration ([Ca ] ) within the physiological range markedly increased NADH level. However, the addition of pyruvate or citrate attenuated the Ca dependence of NADH during the workload transition. Under the simulated in vivo condition where malate, glutamate, pyruvate, citrate and 2-oxoglutarate were used as mitochondrial substrates, the energy metabolites were more stable during the workload transition and NADH level was almost insensitive to [Ca ] . It was revealed that mitochondrial substrates have a significant influence on metabolite constancy during cardiac workload transition, and Ca has only a minor role under physiological conditions.

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“…Third, Beard and his colleagues discovered from experiments using isolated rat heart mitochondria that Ca 2+ at the physiological level did not stimulate flux of NAD(P)H synthesis nor ΔΨ over a wide range of VO 2 (Vinnakota et al . 2011, 2016 b ). Although species differences in intracellular Ca 2+ handling (Bassani et al .…”

Section: Parallel Activation Mechanismmentioning

confidence: 99%

Integration of mitochondrial energetics in heart with mathematical modelling

Takeuchi

Matsuoka

2020

The Journal of Physiology

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Edited by: Russell Hepple = · + + − Mathematical formulation and integration NADH supply OxPhos ATP consumption ADP+Pi ATP NADH NAD + Fatty acids Glucose Lactate CO 2 Contraction Ion pumping Citric acid cycle PDHC ATP production Mitochondria Experimental approachAbstract It has been an unsolved question how cardiac mitochondrial energetics is regulated during working transition. Mathematical modelling is a powerful tool for exploring the complicated networks of mitochondrial metabolism. We summarize the recent progress and remaining questions about mitochondrial energetics in heart, especially focusing on approaches utilizing mathematical modelling. Feedback activation by ADP and/or inorganic phosphate is an old but still attractive hypothesis for explaining the regulation mechanisms of cardiac mitochondrial energetics. However, this hypothesis has not been fully validated by experiments because rises of ADP and/or inorganic phosphate concentrations during cardiac workload increase have not been detected in many experiments. The hypothesis of intracellular energetic units is an extended version of feedback activation, which has a similar problem. The each-step activation hypothesis beautifully reproduces metabolite constancy, although such master regulators have not been identified yet. Ca 2+ has been the most plausible candidate because some of the mitochondrial Ayako Takeuchi started experiments on, and mathematical modelling of, cardiac physiology in Dr A. Noma's lab in 2004. She also carried out structure-function studies of Na + -K + ATPase in Dr D. Gadsby's lab (Rockefeller University, New York). Her main interest is mitochondrial Ca 2+ dynamics and ion channels/transporters. Satoshi Matsuoka started electrophysiological studies of ion transporters in Dr A. Noma's lab in 1990. Since then, he has mainly studied plasma membrane and mitochondrial Na + -Ca 2+ exchangers, and also studies the physiology of cardiomyocytes with mathematical modelling.

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Open-Loop Control of Oxidative Phosphorylation in Skeletal and Cardiac Muscle Mitochondria by Ca2+

Cited by 18 publications

References 35 publications

Skeletal muscle performance in metabolic disease: Microvascular or mitochondrial limitation or both?

Skeletal muscle performance in metabolic disease: Microvascular or mitochondrial limitation or both?

A simulation study on the constancy of cardiac energy metabolites during workload transition

Integration of mitochondrial energetics in heart with mathematical modelling

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