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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.
Highlights
Accumulation of damaged mitochondria is implicated in a number of neurodegenerative disorders, including Parkinson’s disease
Because most of the reported BCL2-associated athanogene 6 (BAG6) functions are restricted to the cytoplasm and the nucleus, we examined whether BAG6 functions in other cellular compartments
Under non-stressed conditions, we did not see any significant differences in the distribution and amounts of mitochondria in BAG6-knockdown cells compared with control cells (Fig. 1Ba,b)
Summary
Accumulation of damaged mitochondria is implicated in a number of neurodegenerative disorders, including Parkinson’s disease. 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. RNA interferencemediated 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. Abbreviations BAG6, BCL2-associated athanogene 6; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; DMSO, dimethyl sulfoxide; EGTA, ethylene glycol tetraacetic acid; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; MAM, mitochondria-associated ER membranes; MFN, mitofusin; PBS, phosphate buffered saline; PINK1, PTEN-induced kinase; siRNA, small interference RNA; SQSTM1, sequestosome 1; TA, tail-anchored; TOMM20, translocase of outer mitochondrial membrane 20; UBX, ubiquitin regulatory X; VCP, valosincontaining protein.
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