Bcl-2-associated athanogene 5 (BAG5) regulates Parkin-dependent mitophagy and cell death

Mitchell L De Snoo,Thomas M Durcan,Victoria Agapova,Minesh Kapadia,Ornella Pellerito,Yu Tong Zhang,Suneil K Kalia,Rebecca Earnshaw,Gerold Schmitt-Ulms,Darren M O’Hara,Matthew Y Tang,Erik L Friesen,Xinzhu Wang,Geneviève Dorval,Edward A Fon,Lorraine V Kalia,Hien Chau

doi:10.1038/s41419-019-2132-x

Abstract

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.

Highlights

Loss-of-function mutations in the genes encoding Parkin, an E3 ubiquitin ligase, and PINK1, a serine/threonine kinase, cause genetic forms of Parkinson’s disease (PD), a neurodegenerative movement disorder characterized by loss of dopaminergic neurons[1,2]
Given that we have previously shown that Bcl-2-associated athanogene 5 (BAG5) interacts with Parkin[16], and that BAG2 and BAG4 have been shown to differentially regulate Parkin recruitment[18,19], we hypothesized that BAG5 regulates Parkin recruitment to depolarized mitochondria
We found that FlagBAG5-positive cells exhibited a significantly reduced proportion of cells displaying GFP-Parkin colocalization with TOM20 compared with dsRed transfected control cells, indicating a potential delay in Parkin recruitment by BAG5 (Fig. 1b)

Summary

Introduction

Loss-of-function mutations in the genes encoding Parkin, an E3 ubiquitin ligase, and PINK1, a serine/threonine kinase, cause genetic forms of Parkinson’s disease (PD), a neurodegenerative movement disorder characterized by loss of dopaminergic neurons[1,2]. Parkin and PINK1 act in concert in a recently defined pathway that leads to the specific autophagic degradation of damaged mitochondria, a process known as mitophagy[3]. In this pathway, PINK1 is stabilized on the surface of damaged mitochondria where it phosphorylates its substrates, Parkin and ubiquitin, which results in the recruitment of Parkin containing oxidized electron transport chain components[11], as well as direct the selective degradation of abnormal protein aggregates from within the mitochondria[12]. Recent work indicates that, under certain circumstances of mitochondrial stress, Parkin and PINK1 promote apoptosis by directing the polyubiquitination and subsequent degradation of the antiapoptotic Bcl-2 family member, Mcl-114,15. The factors that direct Parkin to function as a promoter of cell death have not yet been fully elucidated

Methods

Results

Conclusion