Mitochondrial VDAC, the Na⁺/Ca²⁺ exchanger, and the Ca²⁺ uniporter in Ca²⁺ dynamics and signaling

Mitochondrial Ca²⁺ uptake and release play pivotal roles in cellular physiology by regulating intracellular Ca²⁺ signaling, energy metabolism, and cell death. Ca²⁺ transport across the inner and outer mitochondrial membranes (IMM, OMM, respectively), is mediated by several proteins, including the voltage-dependent anion channel 1 (VDAC1) in the OMM, and the mitochondrial Ca²⁺ uniporter (MCU) and Na⁺-dependent mitochondrial Ca²⁺ efflux transporter, (the NCLX), both in the IMM. By transporting Ca²⁺ across the OMM to the mitochondrial inner-membrane space (IMS), VDAC1 allows Ca²⁺ access to the MCU, facilitating transport of Ca²⁺ to the matrix, and also from the IMS to the cytosol. Intra-mitochondrial Ca²⁺ controls energy production and metabolism by modulating critical enzymes in the tricarboxylic acid (TCA) cycle and fatty acid oxidation. Thus, by transporting Ca²⁺, VDAC1 plays a fundamental role in regulating mitochondrial Ca²⁺ homeostasis, oxidative phosphorylation, and Ca²⁺ crosstalk among mitochondria, cytoplasm, and the endoplasmic reticulum (ER). VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, and apoptosis stimuli induce overexpression of the protein in a Ca²⁺-dependent manner. The overexpressed VDAC1 undergoes oligomerization leading to the formation of a channel, through which apoptogenic agents can be released. Here, we review the roles of VDAC1 in mitochondrial Ca²⁺ homeostasis, in apoptosis, and in diseases associated with mitochondria dysfunction.