title: VDAC-2: Mitochondrial outer membrane regulator masquerading as a channel?
abstract: The voltage-dependent anion channels (VDACs) are the workforce of mitochondrial transport and as such are required for cellular metabolism. The elaborate interplay between mitochondria and the apoptotic pathway supports a role for VDACs as a major regulator of cell death. Although VDAC-1 has an established role in apoptosis and cell homeostasis, the role of VDAC-2 has been controversial. In humans, VDAC-2 is best known for its anti-apoptotic properties. In this Viewpoint, we associate the various functional studies on VDAC-2 with structural reports, to decode its unique behavior. The well-structured N-terminus, compact barrel form, differences in the loop regions, specific transmembrane segments and the abundance of thiols in VDAC-2 enable this isoform to perform a different subset of regulatory functions, establish anti-apoptotic features and contribute to gametogenesis. VDAC-2 structural features that demarcate it from VDAC-1 suggest that this particular isoform is better suited for regulating reactive oxygen species, steroidogenesis and mitochondria-associated endoplasmic reticulum membrane regulatory pathways, with ion transport forming a secondary role. A better understanding of the unique structural features of the VDAC family will aid in the design of inhibitors that could alleviate irregularities in VDAC-controlled pathways.
authors.affiliation: Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Svetlana Rajkumar
authors.initials: SR
authors.lastname: Maurya
authors.affiliation: Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India.
authors.forename: Radhakrishnan
authors.identifier: 0000-0003-1549-7550
authors.initials: R
authors.lastname: Mahalakshmi
mesh_terms: D000818:Animals; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology*; D050996:Voltage-Dependent Anion Channel 2 / Q000502:physiology*
chemical_list: D007473:Ion Channels; C494765:VDAC2 protein, human; D050996:Voltage-Dependent Anion Channel 2
keywords: apoptosis; cysteines; mitochondrial outer membrane; voltage-dependent anion channel; β-barrel proteins