As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson's disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a 'switch' that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.
Conflict of interest statement
The authors declare that they have no conflict of interest.
BAG5 Inhibits Parkin and Enhances Dopaminergic Neuron DegenerationSK Kalia et al. Neuron 44 (6), 931-45. PMID 15603737.Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, are the major cause of early-onset Parkinson's disease (PD). Decreases in parkin acti …
Parkin Sensitizes Toward Apoptosis Induced by Mitochondrial Depolarization Through Promoting Degradation of Mcl-1RG Carroll et al. Cell Rep 9 (4), 1538-53. PMID 25456142.Mitochondrial depolarization promotes Parkin- and PTEN-induced kinase 1 (PINK1)-dependent polyubiquitination of multiple proteins on mitochondrial outer membranes, result …
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- PJT156085/Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
- CGS-M/Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
- CGS-M/Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)