Integration of mitochondrial energetics in heart with mathematical modelling

Abstract

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.

Membrane current evoked by mitochondrial Na+–Ca2+ exchange in mouse heart

“…Mitochondrial Ca 2+ has pivotal roles in mitochondrial metabolism, apoptosis, and cytoplasmic Ca 2+ signaling [1][2][3][4][5]. Mitochondrial Ca 2+ influx is mainly mediated via mitochondrial Ca 2+ uniporter (MCU), and efflux via Na + -Ca 2+ exchanger (NCXm) and H + -Ca 2+ exchanger.…”

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

“…Mitochondria dysfunction has been repeatedly reported in heart diseases and neurological disorders ( 40 – 45 ), but the underlying mechanisms are still not fully understood ( 43 , 46 – 50 ). In this study, our established heart-specific KO Atp8 ( Atp8 MHC-Cre ) and Nd1 ( Nd1 MHC-Cre ) rats displayed growth retardation, short life span, dilated cardiomyopathy, and impaired mitochondria structure.…”

Kinetic Mathematical Modeling of Oxidative Phosphorylation in Cardiomyocyte Mitochondria

“…ADP and inorganic phosphate are substrates of complex V to synthesize ATP. Takeuchi et al [ 40 ] conducted a comprehensive review of modeling the tight regulation of ATP levels via calcium, ADP, and inorganic phosphate dynamics.…”

“…The interactions between these systems are related to cardiomyocyte pathologies such as altered calcium dynamics and electrophysiology, heart failure, ischemic-reperfusion injury, diabetic cardiomyopathy, and chemotherapy-induced cardiomyopathy [ 38 ]. Investigating the complex interactions and inner workings of OXPHOS and related metabolic systems using systems biology approaches and computer simulation models can complement the knowledge gathered from in vitro and in vivo studies, identify candidate mechanisms, and corroborate/propose novel hypotheses [ 39 , 40 , 41 , 42 ]. For these reasons, we review the mathematical modeling of OXPHOS complexes, focusing on cardiomyocyte bioenergetics models.…”