BAG6 promotes PINK1 signaling pathway and is essential for mitophagy

Abstract

Bcl-2-associated athanogen-6 (BAG6) is a nucleocytoplasmic shuttling protein involved in protein quality control. We previously demonstrated that BAG6 is essential for autophagy by regulating the intracellular localization of the acetyltransferase EP300, and thus, modifying accessibility to its substrates (TP53 in the nucleus and autophagy-related proteins in the cytoplasm). Here, we investigated BAG6 localization and function in the cytoplasm. First, we demonstrated that BAG6 is localized in the mitochondria. Specifically, BAG6 is expressed in the mitochondrial matrix under basal conditions, and translocates to the outer mitochondrial membrane after mitochondrial depolarization with carbonyl cyanide m-chlorophenyl hydrazine, a mitochondrial uncoupler that induces mitophagy. In SW480 cells, the deletion of BAG6 expression abrogates its ability to induce mitophagy and PINK1 accumulation. On the reverse, its ectopic expression in LoVo colon cancer cells, which do not express endogenous BAG6, reduces the size of the mitochondria, induces mitophagy, leads to the activation of the PINK1/PARKIN pathway and to the phospho-ubiquitination of mitochondrial proteins. Finally, BAG6 contains two LIR (LC3-interacting Region) domains specifically found in receptors for selective autophagy and responsible for the interaction with LC3 and for autophagosome selectivity. Site-directed 2 of 14 | RAGIMBEAU Et Al.

Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

“…The comprehension of PINK1/Parkin-related mitophagy signaling in colon cancer is of emerging interest. Recent evidence described the role of Bcl-2-associated athanogen-6 induced BAG6 as a novel receptor in the PINK1/Parkin pathway involved in protein quality control [ 35 ]. In BAG6-transfected LoVo cells, the mitophagy process was observed after mitochondrial depolarization and phosphorylation-ubiquitination of mitochondrial proteins [ 35 ].…”

“…Recent evidence described the role of Bcl-2-associated athanogen-6 induced BAG6 as a novel receptor in the PINK1/Parkin pathway involved in protein quality control [ 35 ]. In BAG6-transfected LoVo cells, the mitophagy process was observed after mitochondrial depolarization and phosphorylation-ubiquitination of mitochondrial proteins [ 35 ]. On the contrary, the deletion of this nucleocytoplasmic shuttling protein in SW480 cells abolished mitochondrial mass, mitophagy and PINK1 accumulation [ 35 ].…”

“…In BAG6-transfected LoVo cells, the mitophagy process was observed after mitochondrial depolarization and phosphorylation-ubiquitination of mitochondrial proteins [ 35 ]. On the contrary, the deletion of this nucleocytoplasmic shuttling protein in SW480 cells abolished mitochondrial mass, mitophagy and PINK1 accumulation [ 35 ]. Besides advanced strategies of drug combinations to arrest cancer progression by modulating apoptosis and autophagy [ 36 ], naturally occurring bioactive compounds capable of inducing LC3B-related autophagy and apoptotic cancer death are part of cancer prevention strategies [ 5 ].…”

BAG Family Members as Mitophagy Regulators in Mammals

“…Due to size limitation, only fragmented mitochondria are engulfed into autophagomes [ 48 ]. In basal conditions, BAG6 is located in the mitochondrial matrix; however, after mitochondrial depolarization, it translocates to the OMM and induces mitochondrial fragmentation [ 49 ]. BAG6 also modulates mitochondrial morphology by interacting with the pro-fusion protein MNF2, thus promoting its proteasomal degradation in a cell model where expression of DRP1, a key regulator of fission, is downregulated [ 50 ].…”

Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger

“…BAG2 is also reported to promote mitophagy by inhibiting PINK1 degradation in neurons [ 187 , 188 ], although the role of BAG2 in the heart has not been determined. A recent study demonstrated that BAG6 localizes in the mitochondria matrix but translocates to the MOM after mitochondrial depolarization to enhance PINK1 accumulation at the mitochondria [ 189 ]. In addition, the authors showed that BAG6 functions as a mitophagy receptor by binding to LC3, facilitating mitophagy in cancer cells.…”