Figure 1.

Schematic representation of VDAC1 as a multi-functional protein involved in Ca²⁺ and metabolite transport, energy production and the structural and functional association of mitochondria with the ER. The various functions of VDAC1 in cell and mitochondria functions are presented. These include: (A) Transporting Ca²⁺ across the OMM, thereby modulating Ca²⁺ signaling. In the IMM, Ca²⁺ uptake into the matrix is mediated by a Ca²⁺-selective transporter, the mitochondrial Ca²⁺ uniporter (MCU), regulated by a calcium-sensing accessory subunit (MCU1). Ca²⁺ efflux is mediated by NCLX, a Na⁺/Ca²⁺ exchanger. Ca²⁺ controls energy production via activation of PDH, ICDH, and α KGDH by intra-mitochondrial Ca²⁺, leading to enhanced activity of the citric acid cycle; (B) Control of metabolic cross-talk between the mitochondria and the rest of the cell, by transporting metabolites; (C) Mediating cellular energy production by transporting ATP/ADP and NADH and acyl-CoA from the cytosol to the IMS, and regulating glycolysis via the association with HK; (D) Involvement in structural and functional association with the ER, mediating Ca²⁺ transport from the ER to mitochondria. Key proteins, such as the inositol 3 phosphate receptor type 3 (IP₃R3), the sigma1 receptor (Sig1R), the chaperone HSP70, and glucose-regulated protein 75 (GRP75) are presented; (E) Participation in apoptosis via its oligomerization to form a protein-conducting channel, allowing Cyto c release and cell death; and (F) Mediation of the transfer of fatty acid acyl-CoAs across the OMM to the IMS, where they are converted into acylcarnitine by CPT1a for further processing by β-oxidation. VDAC1 is involved in cholesterol transport as a constituent of a multi-protein complex, the transduceosome, containing Star, TSPO and VDAC1. (G) The permeability transition pore (PTP), composed of VDAC at the OMM, ANT at the IMM and Cyp D in the matrix, allows release of apoptogenic proteins.