The mitochondrial calcium uniporter complex-A play in five acts

Abstract

Mitochondrial Ca²⁺ (mitCa²⁺) uptake controls both intraorganellar and cytosolic functions. Within the organelle, [Ca²⁺] increases regulate the activity of tricarboxylic acid (TCA) cycle enzymes, thus sustaining oxidative metabolism and ATP production. Reactive oxygen species (ROS) are also generated as side products of oxygen consumption. At the same time, mitochondria act as buffers of cytosolic Ca²⁺ (cytCa²⁺) increases, thus regulating Ca²⁺-dependent cellular processes. In pathological conditions, mitCa²⁺ overload triggers the opening of the mitochondrial permeability transition pore (mPTP) and the release of apoptotic cofactors. MitCa²⁺ uptake occurs in response of local [Ca²⁺] increases in sites of proximity between the endoplasmic reticulum (ER) and the mitochondria and is mediated by the mitochondrial Ca²⁺ uniporter (MCU), a highly selective channel of the inner mitochondrial membrane (IMM). Both channel and regulatory subunits form the MCU complex (MCUC). Cryogenic electron microscopy (Cryo-EM) and crystal structures revealed the correct assembly of MCUC and the function of critical residues for the regulation of Ca²⁺ conductance.