VDAC1 at the crossroads of cell metabolism, apoptosis and cell stress

TLDR

VDAC1 is a multifunctional mitochondrial protein located at the outer mitochondrial membrane that regulates cellular energy production, metabolic cross‑talk, and apoptosis by mediating the release of cytochrome c and AIF and interacting with proteins such as hexokinase, Bcl‑2, and Bcl‑xL. This review aims to elucidate VDAC1’s roles in calcium homeostasis, oxidative stress, and its function as a hub protein interacting with over 100 partners. VDAC1 functions as an OMM channel that oligomerizes to form a large pore for apoptotic factor release, regulates calcium flux, and engages metabolic and survival proteins. VDAC1’s position at the intersection of mitochondrial metabolite transport and apoptosis renders it an emerging target for cancer therapeutics.

Abstract

This review presents current knowledge related to VDAC1 as a multi-functional mitochondrial protein acting on both sides of the coin, regulating cell life and death, and highlighting these functions in relation to disease. It is now recognized that VDAC1 does not only play a crucial role in regulating the metabolic and energetic functions of mitochondria. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows the control of metabolic cross-talk between mitochondria and the rest of the cell and also enables its interaction with proteins involved in metabolic and survival pathways. Along with regulating cellular energy production and metabolism, VDAC1 is also involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. VDAC1 functions in the release of apoptotic proteins located in the mitochondrion inter-membranal space via oligomerization to form a large channel that allows passage of cytochrome c and AIF and their release to the cytosol, subsequently apoptotic cell death. VDAC1 also regulates apoptosis via interactions with apoptosis regulatory proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. This review also provide insight into VDAC1 function in Ca2+ homeostasis, oxidative stress, and presents VDAC1 as a hub protein interacting with over 100 proteins. Such interactions enable VDAC1 to mediate and regulate the integration of mitochondrial functions with cellular activities. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target.