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

Mitochondrial Ca uptake and release play pivotal roles in cellular physiology by regulating intracellular Ca signaling, energy metabolism, and cell death. Ca 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 Ca uniporter (MCU) and Na-dependent mitochondrial Ca efflux transporter, (the NCLX), both in the IMM. By transporting Ca across the OMM to the mitochondrial inner-membrane space (IMS), VDAC1 allows Ca access to the MCU, facilitating transport of Ca to the matrix, and also from the IMS to the cytosol. Intra-mitochondrial Ca controls energy production and metabolism by modulating critical enzymes in the tricarboxylic acid (TCA) cycle and fatty acid oxidation. Thus, by transporting Ca, VDAC1 plays a fundamental role in regulating mitochondrial Ca homeostasis, oxidative phosphorylation, and Ca 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 Ca-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 Ca homeostasis, in apoptosis, and in diseases associated with mitochondria dysfunction.