Feedback Regulation and Time Hierarchy of Oxidative Phosphorylation in Cardiac Mitochondria

Vinnakota, Kalyan C.; Bazil, Jason N.; Bergh, Françoise Van den; Wiseman, Robert W.; Beard, Daniel A.

doi:10.1016/j.bpj.2016.01.003

Cited by 26 publications

(33 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most recently Vinnakota et al . ( a ) reported that P i did not modulate the activity of Complex III in isolated mitochondria, in conflict with a previous report by Bose et al . (2013).…”

Section: Discussioncontrasting

confidence: 78%

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

Saito

Takeuchi

Himeno

et al. 2016

The Journal of Physiology

View full text Add to dashboard Cite

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.

show abstract

“…Most recently Vinnakota et al . ( a ) reported that P i did not modulate the activity of Complex III in isolated mitochondria, in conflict with a previous report by Bose et al . (2013).…”

Section: Discussioncontrasting

confidence: 78%

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

Saito

Takeuchi

Himeno

et al. 2016

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…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 Metmentioning

confidence: 99%

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

2018

View full text Add to dashboard Cite

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

show abstract

“…Hence, in the simulations, when O 2 is zero and the respiratory chain is blocked, NAD becomes highly reduced but not to 100%, due to the reversibility of DH. (b) In experimental measurements, the signal of NAD in the presence of an inhibitor of the respiratory chain or in anoxia is assigned to 100% reduction (e.g., ), although NADH is also used by other reactions.…”

Section: Resultsmentioning

confidence: 99%

“…However recently, Vinnakota challenged the Pi activation with an indirect experimental approach, and Chess et al . could disprove the particular mechanism (crossover of reduction states within complex III) proposed by Bose et al .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive mathematical model of oxidative phosphorylation valid for physiological and pathological conditions

2017

View full text Add to dashboard Cite

We developed a mathematical model of oxidative phosphorylation (OXPHOS) that allows for a precise description of mitochondrial function with respect to the respiratory flux and the ATP production. The model reproduced flux-force relationships under various experimental conditions (state 3 and 4, uncoupling, and shortage of respiratory substrate) as well as time courses, exhibiting correct P/O ratios. The model was able to reproduce experimental threshold curves for perturbations of the respiratory chain complexes, the F F -ATP synthase, the ADP/ATP carrier, the phosphate/OH carrier, and the proton leak. Thus, the model is well suited to study complex interactions within the OXPHOS system, especially with respect to physiological adaptations or pathological modifications, influencing substrate and product affinities or maximal catalytic rates. Moreover, it could be a useful tool to study the role of OXPHOS and its capacity to compensate or enhance physiopathologies of the mitochondrial and cellular energy metabolism.

show abstract

Feedback Regulation and Time Hierarchy of Oxidative Phosphorylation in Cardiac Mitochondria

Cited by 26 publications

References 46 publications

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

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

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

Comprehensive mathematical model of oxidative phosphorylation valid for physiological and pathological conditions

Contact Info

Product

Resources

About