The mitochondrial calcium uniporter in the heart: energetics and beyond

Ca²⁺ and mitochondria are inextricably linked to cardiac function and dysfunction. Ca²⁺ is central to cardiac excitation-contraction coupling and stimulates mitochondrial energy production to fuel contraction. Under pathological conditions of dysregulated Ca²⁺ cycling, mitochondrial Ca²⁺ overload activates cellular death pathways. Thus, in the cardiomyocyte, the mitochondrial Ca²⁺ microdomain is where contraction, energy and death collide. A key component of mitochondrial Ca²⁺ signalling is the mitochondrial Ca²⁺ uniporter complex (uniplex), an inner membrane Ca²⁺ transporter and major pathway of mitochondrial Ca²⁺ entry. Once known only as the unidentified target for ruthenium red and related compounds, in recent years, the uniplex has evolved into a complex multiprotein assembly. The identification of the molecular constituents of the uniplex has made possible the generation of targeted genetic models to interrogate uniplex function in vivo. This review will summarize our current understanding of the molecular structure of the uniplex, its impact on mitochondrial energetics and cardiac physiology, its contribution to cardiomyocyte death, and its expanding roles in cardiac biology.