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    Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination

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    Author
    Oshima, Yumiko
    Cartier, Etienne
    Boyman, Liron
    Verhoeven, Nicolas
    Polster, Brian M
    Huang, Weiliang
    Kane, Maureen
    Lederer, W Jonathan
    Karbowski, Mariusz
    Date
    2021-04-14
    Journal
    Journal of Cell Biology
    Publisher
    Rockefeller University Press
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1083/jcb.202006043
    Abstract
    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.
    Keyword
    Parkin
    Mitochondrial Membranes
    Mitophagy
    Ubiquitination
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/15504
    ae974a485f413a2113503eed53cd6c53
    10.1083/jcb.202006043
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