Figure 3.

VDAC1 function in cell death. Different models proposed for the release of apoptogenic proteins, such as Cyto c (gold balls) and apoptosis-inducing factor (AIF), from the mitochondrial inter-membrane space to the cytosol, leading to apoptosis. These models include (a) VDAC1 closure and outer mitochondrial membrane (OMM) rupture serving as the Cyto c release pathway—prolonged VDAC1 closure leads to mitochondrial matrix swelling and OMM rupture, resulting in the appearance of a non-specific release pathway for apoptogenic proteins; (b) a permeability transition pore (PTP) provides the apoptogenic protein release pathway—a large conductance pore-forming complex, the PTP, composed of VDAC1 in the OMM, adenine nucleotide translocase in the inner mitochondrial membrane (IMM), and cyclophilin D (CyD) in the matrix, allows apoptogenic protein release; (c) Bax activation, followed by its oligomerization, results in OMM permeabilization—upon apoptosis induction, Bax becomes associated with mitochondria as a large oligomer/complex forming a Cyto c-conducting channel in the OMM; (d) a pore is formed by oligomerized forms of Bax and Bak—Bax/Bak oligomerization, supposedly activated by BH3-only proteins (e.g., Bid), results in OMM permeabilization and Cyto c release; (e) a Bax- and VDAC1-based hetro-oligomer mediates Cyto c release—the interaction of pro-apoptotic proteins (Bax/Bak) with VDAC1 forms a cytochrome c (Cyto c) release pathway; (f) mitochondrial apoptosis-inducing channel (MAC) as the release pathway—MAC offers a high-conductance channel and a putative Cyto c release channel; (g) oligomeric VDAC1 as a channel for the release of apoptotic proteins—a protein-conducting channel is formed within a VDAC1 homo-oligomer, allowing Cyto c release and apoptotic cell death; (h) mitochondrial Ca²⁺ overload induces apoptosis—following Ca²⁺ overload in the matrix, Ca²⁺ transport mediated by VDAC1 across the OMM and by the mitochondrial Ca²⁺ uniporter (MCU) in the IMM leads to dissipation of the membrane potential, mitochondria swelling, PTP opening, Cyto c release, and apoptotic cell death. PTP opening is also accompanied by an efflux of the accumulated Ca²⁺ into the cytosol.