Phospholipid Scramblase Activity of VDAC Dimers: New Implications for Cell Death, Autophagy and Ageing

Voltage-dependent anion channels (VDACs) are important proteins of the outer mitochondrial membrane (OMM). Their beta-barrel structure allows for efficient metabolite exchange between the cytosol and mitochondria. VDACs have further been implicated in the control of regulated cell death. Historically, VDACs have been pictured as part of the mitochondrial permeability transition pore (MPTP). New concepts of regulated cell death involving VDACs include its oligomerisation to form a large pore complex in the OMM; however, alternative VDAC localisation to the plasma membrane has been suggested in the literature and will be discussed regarding its potential role during cell death. Very recently, a phospholipid scramblase activity has been attributed to VDAC dimers, which explains the manifold lipidomic changes observed in VDAC-deficient yeast strains. In this review, I highlight the recent advances regarding VDAC's phospholipid scramblase function and discuss how this new insight sheds new light on VDAC's implication in regulated cell death, autophagy, and ageing.