VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease

• Published in: Cell calcium (Edinburgh) 2021-03, Vol.94, p.102356-102356, Article 102356
• Main Authors: Rosencrans, William M., Rajendran, Megha, Bezrukov, Sergey M., Rostovtseva, Tatiana K.
• Format: Article
• Language: English
• Subjects: Animals; Biophysical Phenomena; Calcium Channels - metabolism; Calcium Signaling; Disease; Humans; Ion selectivity; Mitochondria - metabolism; Mitochondrial associated membrane; Mitochondrial outer membrane; Protein-protein interaction; Voltage gating; Voltage-dependent anion channel; Voltage-Dependent Anion Channels - metabolism; α-synuclein
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/j.ceca.2021.102356

[Display omitted] •VDAC plays an important role in mitochondrial calcium transport, regulation, and signaling.•VDAC is part of multi-protein complexes linking it to calcium channels in other organelles for efficient calcium exchange.•VDAC calcium transport can be regulated by voltage gating and by its interaction with proteins such as α-synuclein.•Calcium transport through VDAC is isoform specific. Voltage-dependent anion channel (VDAC), the most abundant mitochondrial outer membrane protein, is important for a variety of mitochondrial functions including metabolite exchange, calcium transport, and apoptosis. While VDAC’s role in shuttling metabolites between the cytosol and mitochondria is well established, there is a growing interest in understanding the mechanisms of its regulation of mitochondrial calcium transport. Here we review the current literature on VDAC’s role in calcium signaling, its biophysical properties, physiological function, and pathology focusing on its importance in cardiac diseases. We discuss the specific biophysical properties of the three VDAC isoforms in mammalian cells—VDAC 1, 2, and 3—in relationship to calcium transport and their distinct roles in cell physiology and disease. Highlighting the emerging evidence that cytosolic proteins interact with VDAC and regulate its calcium permeability, we advocate for continued investigation into the VDAC interactome at the contact sites between mitochondria and organelles and its role in mitochondrial calcium transport.