The mitochondrial calcium uniporter in the heart: energetics and beyond

Abstract

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.

Keywords: calcium mitochondria; cell death; energy; heart; mitochondria.

Figure 1. Mitochondrial Ca²⁺ signalling in cardiac metabolic contraction coupling

In the cardiac fight or flight response, catecholamine signalling leads to increased cytosolic Ca²⁺ that drives enhanced contraction. This enhanced contraction is coupled to elevated mitochondrial energetic output as the uniplex transports Ca²⁺ into the mitochondrial matrix. Ca²⁺ activates the TCA cycle enzymes pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and α‐ketoglutarate dehydrogenase (αKGDH), as well as the mitochondrial ATP synthase (complex V). Cumulatively, this results in increased mitochondrial ATP production that fuels contraction. IMM, inner mitochondrial membrane; IMS, intermembrane space; OMM, outer mitochondrial membrane.

Figure 2. Ca²⁺ overload‐induced cell death in the heart

Pathological conditions such as cardiac ischaemia–reperfusion injury result in cytosolic Ca²⁺ overload. The uniplex transports Ca²⁺ into the mitochondrial matrix, resulting in activation and opening of the MPTP. MPTP opening causes inner mitochondrial membrane (IMM) permeabilization, loss of mitochondrial membrane potential (ΔΨ) and impaired ATP synthesis. IMM permeabilization also causes mitochondrial (MITO) swelling and rupture, which ultimately results in cardiomyocyte death. IMS, intermembrane space; OMM, outer mitochondrial membrane.