Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination
Author
Oshima, YumikoCartier, Etienne
Boyman, Liron
Verhoeven, Nicolas
Polster, Brian M
Huang, Weiliang
Kane, Maureen
Lederer, W Jonathan
Karbowski, Mariusz
Date
2021-04-14Journal
Journal of Cell BiologyPublisher
Rockefeller University PressType
Article
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Here, we report that acute reduction in mitochondrial translation fidelity (MTF) causes ubiquitination of the inner mitochondrial membrane (IMM) proteins, including TRAP1 and CPOX, which occurs selectively in mitochondria with a severed outer mitochondrial membrane (OMM). Ubiquitinated IMM recruits the autophagy machinery. Inhibiting autophagy leads to increased accumulation of mitochondria with severed OMM and ubiquitinated IMM. This process occurs downstream of the accumulation of cytochrome c/CPOX in a subset of mitochondria heterogeneously distributed throughout the cell ("mosaic distribution"). Formation of mosaic mitochondria, OMM severing, and IMM ubiquitination require active mitochondrial translation and mitochondrial fission, but not the proapoptotic proteins Bax and Bak. In contrast, in Parkin-overexpressing cells, MTF reduction does not lead to the severing of the OMM or IMM ubiquitination, but it does induce Drp1-independent ubiquitination of the OMM. Furthermore, high-cytochrome c/CPOX mitochondria are preferentially targeted by Parkin, indicating that in the context of reduced MTF, they are mitophagy intermediates regardless of Parkin expression. In sum, Parkin-deficient cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that involves the severing of the OMM and autophagy targeting ubiquitinated IMM proteins. © 2021 Oshima et al.Rights/Terms
© 2021 Oshima et al.Identifier to cite or link to this item
http://hdl.handle.net/10713/15504ae974a485f413a2113503eed53cd6c53
10.1083/jcb.202006043
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