Excitation-Metabolism Coupling in Mouse Heart

Abstract

A beating heart must balance energy consumption with production. This balance requires cellular ATP production to respond dynamically to changes in cardiac output and energy demand. While it is well understood that mitochondrial oxidative phosphorylation serves as the primary pathway for ATP production in heart, the mechanisms that govern the regulation of mitochondrial metabolism remain unclear. Calcium (Ca2+), specifically Ca2+ in the mitochondrial matrix ([Ca2+]m), has been implicated as a likely signaling pathway for this regulation. [Ca2+]m has been suggested to regulate nearly every stage of mitochondrial metabolism including the activity of the tricarboxylic acid cycle (TCA) via Ca2+-sensitive dehydrogenases (DHOs), critical proteins in the electron transport chain (ETC), and even the F1/F0 ATP synthase itself. Here we expand our local control mathematical model of excitation-contraction coupling in mouse heart to investigate excitation-metabolism coupling. The model features mechanistic initiation and termination of Ca2+ sparks and cytosolic Ca2+ ([Ca2+]i) transients in a system that maintains sarcoplasmic reticulum (SR) Ca2+ pump/leak balance. Mitochondrial Ca2+ uptake and export is simulated using experimentally constrained formulations of the mitochondrial Ca2+ uniporter (MCU) and the mitochondrial sodium/Ca2+ exchanger (NCLX). The model employs key mechanisms of ATP consumption (i.e. SR Ca2+ ATPase and myosin ATPase) and buffering (phosphocreatine) as well as a Ca2+ dependent model for mitochondrial ATP generation. We investigated mitochondrial Ca2+ dynamics at physiological pacing frequencies for mouse heart and show that changes in ATP consumption can be translated to increased energy production through [Ca2+]m signals. Our model provides new insights into mitochondrial Ca2+ dynamics and how these [Ca2+]m signals may function to preserve energy homeostasis in the face of increased demand.