Juxtaposition of Mitochondria to the Ca²⁺ Release Site is Crucial for the Cardiac Energy Balance—A 3-D Simulation Study of Cardiomyocyte—

Abstract

Recent studies revealed that Ca²⁺not only regulates the contraction of cardiomyocytes, but can also function as a signal to stimulate ATP production by the mitochondria. However, spatio-temporal resolutions of current experimental techniques limit our understanding on this issue. This study employs our 3D cardiomyocyte model based on the finite element method (Okada et al. AJP 2005) and has been extended to include the detailed subcellular structure including the sarcolemma with t-tubule system, sarcoplasmic reticulum, myofibrils and mitochondria. Elementary processes involved in the electrophysiology, contraction and ATP metabolism are spatially arranged, and the multiple reaction diffusion equations for Ca²⁺and energy metabolites, and contraction were solved simultaneously. We specifically examined the effect of the gap distance between mitochondria and Ca²⁺release site. Our model revealed that increasing the gap distance induced a severe energetic derangement due to phosphate accumulation, resulting in contractile failure under tachycardic electrical pacing at 3Hz. Juxtaposition of the mitochondria to the Ca²⁺release site is crucial for rapid signal transmission to maintain cardiac energy balance. Realistic 3-D model of cardiac excitation-contraction and metabolism provides a powerful tool for the study of cardiac function by expanding the temporal and spatial resolution beyond the limit in experimental approaches.