Deciphering the role of mitochondrial cytochrome C oxidase subunit 4 in cardiac health and disease.

Cardiovascular diseases (CVDs) are the primary cause of mortality across the globe, making maintaining cardiac health and homeostasis imperative. The cardiac muscle cells have a 30% stake of the area occupied by mitochondria. The efficient generation of ATP, despite metabolic and other cellular shifts, is crucial for maintaining sufficient blood flow throughout the system. Therefore, maintaining mitochondrial health by balancing the levels of intracellular reactive oxygen species (ROS) and quality control systems is vital for cardiac cell survival. This review highlights the role of cytochrome c oxidase subunit 4 (COX4), which is primarily located in the mitochondrial electron transport chain, in the context of the heart. There are two isoforms, i.e., COX4-1 and COX4-2. The intricate balance between the two isoforms combats cellular stress while maintaining efficient ATP generation through oxidative phosphorylation. However, persistent stress impairs the ability of COX4 to dynamically shift between isoforms, resulting in massive ROS production and less efficient mitochondrial respiration, which ultimately hampers cardiac function. The subsequent review highlights the role of COX4, its dynamic isoform shifts, and the contribution of COX-4 to cardiac physiology, as well as its contribution to date in aggravating CVDs. Additionally, compounds capable of modulating COX4 in cardiac disease conditions both preclinically as well as clinically are being explored.