VDAC1 functions in Ca2+ homeostasis and cell life and death in health and disease

Cell Calcium. 2018 Jan;69:81-100. doi: 10.1016/j.ceca.2017.06.007. Epub 2017 Jun 23.

Abstract

In the outer mitochondrial membrane (OMM), the voltage-dependent anion channel 1 (VDAC1) serves as a mitochondrial gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell. VDAC1 also functions in cellular Ca2+ homeostasis by transporting Ca2+ in and out of mitochondria. VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, contributing to the release of apoptotic proteins located in the inter-membranal space (IMS) and regulating apoptosis via association with pro- and anti-apoptotic members of the Bcl-2 family of proteins and hexokinase. VDAC1 is highly Ca2+-permeable, transporting Ca2+ to the IMS and thus modulating Ca2+ access to Ca2+ transporters in the inner mitochondrial membrane. Intra-mitochondrial Ca2+ controls energy metabolism via modulating critical enzymes in the tricarboxylic acid cycle and in fatty acid oxidation. Ca2+ also determines cell sensitivity to apoptotic stimuli and promotes the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca2+ mediates apoptosis is not known. Here, the roles of VDAC1 in mitochondrial Ca2+ homeostasis are presented while emphasizing a new proposed mechanism for the mode of action of pro-apoptotic drugs. This view, proposing that Ca2+-dependent enhancement of VDAC1 expression levels is a major mechanism by which apoptotic stimuli induce apoptosis, position VDAC1 oligomerization at a molecular focal point in apoptosis regulation. The interactions of VDAC1 with many proteins involved in Ca2+ homeostasis or regulated by Ca2+, as well as VDAC-mediated control of cell life and death and the association of VDAC with disease, are also presented.

Keywords: Bcl-xL; Bcl2; Ca(2+) homeostasis; Hexokinase; Mitochondria; Oligomerization; VDAC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis*
  • Calcium / metabolism*
  • Cell Survival
  • Disease*
  • Health*
  • Homeostasis*
  • Humans
  • Voltage-Dependent Anion Channel 1 / chemistry
  • Voltage-Dependent Anion Channel 1 / metabolism*

Substances

  • Voltage-Dependent Anion Channel 1
  • Calcium