Regulation of cardiac cellular bioenergetics: mechanisms and consequences
Open Access
- 30 July 2015
- journal article
- research article
- Published by Wiley in Physiological Reports
- Vol. 3 (7), e12464
- https://doi.org/10.14814/phy2.12464
Abstract
The regulation of cardiac cellular bioenergetics is critical for maintaining normal cell function, yet the nature of this regulation is not fully understood. Different mechanisms have been proposed to explain how mitochondrial ATP production is regulated to match changing cellular energy demand while metabolite concentrations are maintained. We have developed an integrated mathematical model of cardiac cellular bioenergetics, electrophysiology, and mechanics to test whether stimulation of the dehydrogenase flux by Ca2+ or Pi, or stimulation of complex III by Pi can increase the rate of mitochondrial ATP production above that determined by substrate availability (ADP and Pi). Using the model, we show that, under physiological conditions the rate of mitochondrial ATP production can match varying demand through substrate availability alone; that ATP production rate is not limited by the supply of reducing equivalents in the form of NADH, as a result of Ca2+ or Pi activation of the dehydrogenases; and that ATP production rate is sensitive to feedback activation of complex III by Pi. We then investigate the mechanistic implications on cytosolic ion homeostasis and force production by simulating the concentrations of cytosolic Ca2+, Na+ and K+, and activity of the key ATPases, SERCA pump, Na+/K+ pump and actin-myosin ATPase, in response to increasing cellular energy demand. We find that feedback regulation of mitochondrial complex III by Pi improves the coupling between energy demand and mitochondrial ATP production and stabilizes cytosolic ADP and Pi concentrations. This subsequently leads to stabilized cytosolic ionic concentrations and consequentially reduced energetic cost from cellular ATPases.Funding Information
- NIH (P50-GM094503)
- Health Research Council of New Zealand (11/585)
This publication has 44 references indexed in Scilit:
- Role of Mitochondrial Ca2+ in the Regulation of Cellular EnergeticsBiochemistry, 2012
- Stimulatory Effects of Calcium on Respiration and NAD(P)H Synthesis in Intact Rat Heart Mitochondria Utilizing Physiological Substrates Cannot Explain Respiratory Control in VivoOnline Journal of Public Health Informatics, 2011
- A Metabolite-Sensitive, Thermodynamically Constrained Model of Cardiac Cross-Bridge Cycling: Implications for Force Development during IschemiaBiophysical Journal, 2010
- Strong Inference for Systems BiologyPLoS Computational Biology, 2009
- Experimentally observed phenomena on cardiac energetics in heart failure emerge from simulations of cardiac metabolismProceedings of the National Academy of Sciences of the United States of America, 2009
- A Thermodynamic Model of the Cardiac Sarcoplasmic/Endoplasmic Ca2+ (SERCA) PumpBiophysical Journal, 2009
- Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic heartsJournal Of Physiology-London, 2008
- Approximate Model of Cooperative Activation and Crossbridge Cycling in Cardiac Muscle Using Ordinary Differential EquationsBiophysical Journal, 2008
- A Biophysical Model of the Mitochondrial Respiratory System and Oxidative PhosphorylationPLoS Computational Biology, 2005
- Respiratory control in the glucose perfused heartFEBS Letters, 1987