Figure 2.

Structures of VDAC1, TSPO and their structural and functional complex (A) Crystal structure of dimeric Bacillus cercus TSPO (PDB ID: 4RYI) bound to PK11195. This structure is in good agreement with dimeric Rhodobacter sphaeroides TSPO (PDB ID:4UC3) and Homo sapiens TSPO structures solved with cholesterol analog PK11195 (PDB ID: 2MGY). Monomers of TSPO are in green and cyan, while PK11195 is in red [29]. (B) Crystal structure of human VDAC1 (PDB ID: 5XDN): (a) Monomeric VDAC1, (b) the dimeric form of human VDAC1. The N-terminal α-helix is in blue, cholesterol is in red, and E73 is in magenta. Cholesterol was manually docked for visual purposes [35]. (C) Proposed model for VDAC1-TSPO-associated functions: (a) In the OMM, VDAC1 and TSPO form dimers and associate with cholesterol. VDAC1 can be associated with hexokinase and anti-apoptotic proteins. TSPO is associated with anti-mitophagy partners to inhibit autophagy. Upon increased [Ca²⁺], acidification occurs, which in turn increases [ROS]. (b) Increased acidification, Ca²⁺ or ROS levels lead to VDAC1 oligomerization, concomitant with detachment of VDAC1 and TSPO-associated proteins. VDAC1 oligomers (likely hexamers) now create a large channel allowing the release of cytochrome c (Cyto c) from the IMS to the cytosol, activating apoptosis. TSPO is likely to stabilize the newly formed VDAC1 oligomer. (D) TSPO and VDAC1 sequences with the GXXXG motif labeled, and E73 in VDAC1 and the cholesterol-binding site in TSPO and the ATG8-binding motif (WYAGL, green) are also indicated.