期刊
JOURNAL OF CELL BIOLOGY
卷 220, 期 6, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202006043
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资金
- National Institutes of Health [R01GM129584, R21NS096538, 1R01HL142290]
- Center for Biomedical Engineering and Technology
- University of Maryland School of Pharmacy Mass Spectrometry Center [SOP1841-IQB2014]
This study demonstrates that acute reduction in mitochondrial translation fidelity leads to ubiquitination of inner mitochondrial membrane proteins, recruitment of the autophagy machinery, and potential degradation of mitochondria through Parkin-mediated or Drp1-mediated pathways.
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.
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