BAG6 deficiency induces mis‐distribution of mitochondrial clusters under depolarization

Abstract

Accumulation of damaged mitochondria is implicated in a number of neurodegenerative disorders, including Parkinson's disease. Therefore, the machinery for mitochondrial quality control is important for the prevention of such diseases. It has been reported that Parkin‐ and p62/sequestosome 1 (SQSTM1)‐mediated clustering and subsequent elimination of damaged mitochondria (termed mitophagy) are critical for maintaining the quality of mitochondria under stress induced by uncoupling agents such as carbonyl cyanide m ‐chlorophenyl hydrazone. However, the molecular mechanisms underlying mitochondrial translocation to the perinuclear region during mitophagy have not been adequately addressed to date. In this study, we found that BCL2‐associated athanogene 6 (BAG6; also known as BAT3 or Scythe) is required for this process. Indeed, RNA interference‐mediated depletion of endogenous BAG6 prevented Parkin‐dependent relocalization of mitochondrial clusters to the perinuclear cytoplasmic region, whereas BAG6 knockdown did not affect the translocation of Parkin and p62/SQSTM1 to the depolarized mitochondria and subsequent aggregation. These results suggest that BAG6 is essential for cytoplasmic redistribution, but not for clustering, of damaged mitochondria.

Phloretin alleviates palmitic acid-induced oxidative stress in HUVEC cells by suppressing the expression of LncBAG6-AS

“…44 Particularly, the deficiency of BAG6 can reduce the mitochondria size, lead to the mis-distribution of mitochondrial clusters under depolarization, induce activation of the PINK1/PARKIN pathway and the phospho-ubiquitination of mitochondrial proteins, which abrogates the ability to induce mitophagy. 46,47 As an excellent regulator of autophagy, BAG6 plays an important role in the response of organisms to stress. 48 For instance, BAG6 is required for plant defense against pathogens and tolerance to abiotic stresses, and plays a key role in coordinating neurotranscriptomic changes in the hypothalamus.…”

BAG6 promotes PINK1 signaling pathway and is essential for mitophagy

“…8,25 It is also established that BAG6 is important for the cytoplasmic redistribution of damaged mitochondria in a PARKIN-dependent manner. 19 Interestingly, other BAG family members are also involved in PINK1/PARKIN signaling and mitochondrial quality control. BAG2 stabilizes PINK1 by decreasing its ubiquitination and allowing mitophagy induction.…”

“…18 BAG6 is also involved in the PARKIN-dependent cytoplasmic redistribution of damaged mitochondria. 19 In this work, we investigated BAG6 role in the regulation of mitophagy after mitochondrial depolarization. We first demonstrated that BAG6 is present in the mitochondria of all the tested cell lines (SW480, MEFs, HEK293T, and in BAG6transfected null cells LoVo).…”

Chronic treatment with the complex I inhibitor MPP+ depletes endogenous PTEN-induced kinase 1 (PINK1) via up-regulation of Bcl-2–associated athanogene 6 (BAG6)

“…Bag6 acts as a co-chaperone, negatively regulating HSP70's protein folding capacity (29), in opposition to BAG2 and BAG5. BAG6 acts to target misfolded proteins for proteasomal degradation (62), regulates the distribution of damaged mitochondria (63), and stabilizes the apoptosis inducing factor (AIF) (64), which has been implicated in MPP+ toxicity (65). BAG6 knockout neurons are resistant to ER-stress induced cell death (66).…”