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

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.

Kill one or kill the many: interplay between mitophagy and apoptosis

“…Much like PINK1, Parkin has been described as a neuroprotective agent (Feany and Pallanck 2003). Several interactions with apoptotic proteins have been described, including BCL-x L and BAG5 (De Snoo et al 2019;Hollville et al 2014). Parkin has also been suggested to directly influence apoptosis by ubiquitinating the BH3-binding site of BAK (Bernardini et al 2019).…”

BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62

“…Interestingly, unlike the interaction between BAG5 and p62, the association of BAG5 with this complex was at least partially facilitated by Hsp70 ( Beilina et al, 2014 ). More recently, we have demonstrated that BAG5 also modulates parkin-dependent mitophagy suggesting that this co-chaperone may have a more general role in regulating these processes ( De Snoo et al, 2019 ). Further investigation will be required to understand the mechanisms by which this occurs and the role that other BAG proteins may play in these complex intracellular processes required to maintain proteostasis.…”

“…Considering that BAG5 functionally interacts with LRRK2 to promote turnover of the TGN ( Beilina et al, 2014 ) and inhibits parkin-mediated mitophagy ( De Snoo et al, 2019 ), it may also be possible that BAG5 has a downstream inhibitory effect on autophagic flux, which, in turn, slows the degradation of p62 and alpha-synuclein via the ALP and promotes the accumulation of p62 and alpha-synuclein aggregates ( Wu et al, 2015 ). This notion is supported by the reduction in alpha-synuclein oligomers, soluble p62 protein levels, and perinuclear p62 aggregates following BAG5 KD.…”

“…BAG5 also interacts with and inhibits the ubiquitin E3 ligase activities of parkin and C-terminal Hsp70 interacting protein (CHIP) ( Kalia et al, 2004 , 2011 ). The inhibition of Hsp70, parkin, and CHIP by BAG5 disrupts proteostasis, mitophagy ( De Snoo et al, 2019 ), and promotes the formation of alpha-synuclein oligomers, as well as other protein aggregates, which contribute to neuronal death ( Kalia et al, 2013 ). Consistent with these findings, BAG5 was found to promote dopaminergic neuron death in the substantia nigra in rodent models of PD ( Kalia et al, 2004 ) and interact with other PD relevant proteins including LRRK2, PINK1, and DJ-1 ( Beilina et al, 2014 ; Wang et al, 2014 ; Qin et al, 2017 ; Tan et al, 2019 ; De Snoo et al, 2019 ).…”

Plant Mitophagy in Comparison to Mammals: What Is Still Missing?

“…Recently, another study also demonstrated that BAG3 may promote mitophagy by recruiting Parkin to the depolarized mitochondria [ 135 ]. Conversely, BAG4 and BAG5 have been implicated in disturbing the translocation of PARKIN to the mitochondria, thus suppressing mitophagy [ 139 , 140 ]. Of note, BAG5 directly binds to Parkin to suppress its E3 ligase activity for mitophagy, but promotes Parkin-mediated proteolysis degradation for PCD upon depolarization of mitochondria, indicating a role of BAG5 in switching the pro-survival and pro-death activity of Parkin [ 139 ].…”