Voltage-dependent Anion Channels (VDACs) Recruit Parkin to Defective Mitochondria to Promote Mitochondrial Autophagy

Abstract

Background: Parkin is recruited to defective mitochondria to promote degradation by an autophagy mechanism (mitophagy). Results: VDACs specifically interact with Parkin on defective mitochondria and are required for efficient targeting of Parkin to mitochondria and subsequent mitophagy. Conclusion: VDACs recruit Parkin to defective mitochondria. Significance: A novel mechanistic aspect of Parkin-dependent mitophagy is proposed that may be relevant to Parkinson disease.

The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance

“…18 Such a situation may explain why we did not detect FRET between VDAC1 and PARK2, which based on previous studies should interact. 11,31,34,35 Our findings provide evidence that the TOMM machinery is a switch in the mitochondrial clearance program regulated by the PINK1-PARK2 pathway. They suggest that proteolytic destabilization of the TOMM core complex follows upon the recruitment of PARK2 and acts as the molecular trigger that initiates the degradation of proteins of the OMM and intermembrane space.…”

“…This is a more quantitative method for estimating mitochondrial loss than the simple scoring of cells with or without labeling, a method commonly used by researchers in the field. [8][9][10]14,15,18,[28][29][30][31] With this method, CCCP treatment decreased PMPCB staining in cells overproducing PARK2 by nearly 80%, validating the approach and demonstrating that it is more sensitive than cell scoring. This decrease was completely reversed when PINK1 was downregulated.…”

“…VDACs are excellent candidates, since they have been identified as major partners of PARK2 in cells treated with CCCP and may play a role in mitophagy. 11,31,34,35 These channels are abundant OMM proteins and may thus still be available to interact with PARK2 once the initial phase of mitochondrial degradation is launched. The degradation of the entire OMM may indeed not be necessary for entry into the second phase, since mitochondria with a largely intact OMM are found inside autophagosomes in cells treated with CCCP.…”

Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Phosphorylation by Protein Kinase Cδ (PKCδ) Inhibits Mitochondria Elimination by Lysosomal-like Structures following Ischemia and Reoxygenation-induced Injury

“…Phosphatase and tensin homolog-induced putative kinase protein 1 (PINK1) and Parkin have been found to be involved in mitophagy as well (6,38). In this model, VDACs and mitofusin 2 (Mfn2) were very recently identified as mitochondrial docking sites for recruitment of Parkin from cytosol to mitochondria (39,40). Although most of these studies focus on macroautophagy, our studies suggest that GAPDHinduced mitophagy occurs by what appears to be a micromitophagy process and is independent of macroautophagy.…”

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

“…In addition to the Pink1/Parkin system, several other proteins (e.g. valosincontaining protein (VCP), the p62 protein, microtubule-associated protein 1 light chain (LC3), the Bcl2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3), the mitochondrial voltage-dependent anion channel (VDAC) and the Nix protein) have been implicated in mitophagy induction, regulation and execution but these are discussed elsewhere [125][126][127][128].…”