Figure 1.

Under physiological conditions, Ca²⁺ regulates excitation–contraction coupling, mitochondrial energetics, and ROS production in cardiomyocytes. In cardiomyocytes, action potential causes Ca²⁺ to enter cells from L-type Ca²⁺ channels (Ica, L), and the influx of Ca²⁺ activates Ryanodine Type 2 (RyR2) on the sarcoplasmic reticulum (SR), resulting in a large release of Ca²⁺ from the SR and subsequent binding to troponin C promoting myofilament cross-bridge formation, which causes cardiac contraction. During systole, Ca²⁺ enters SR via SR Ca²⁺-ATPase (SERCA) and exits the extracellular space via the Na⁺/Ca²⁺ exchanger (NCX). Mitochondria take up Ca²⁺ through MCU, and Ca²⁺ activate two key enzymes, isocratic dehydrogenase, and α-ketoglutarate dehydrogenase, of the TCA cycle and regenerate NADH⁺ from NAD. This causes electrons to move along the electron transfer chain (ETC) from complex I to complex IV. Complexes I, III, and IV pump protons (H⁺) into the intermembrane space, forming proton-motive forces bearing electrochemical potential and a proton gradient. Compound V converts ADP to ATP under proton drive. ATP is released into the cytoplasm through the adenine nucleoside transporters (ANT) on the inner membrane of mitochondria.