Parkin-independent mitophagy via Drp1-mediated outer membrane severing and inner membrane ubiquitination
| Autor: | Brian M. Polster, Maureen A. Kane, Nicolas Verhoeven, Yumiko Oshima, W. Jonathan Lederer, Liron Boyman, Etienne Cartier, Weiliang Huang, Mariusz Karbowski |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Dynamins
Mitochondrial translation Ubiquitin-Protein Ligases Mitochondrion Biology Biochemistry Mitochondrial Dynamics Article Parkin Mitochondrial Proteins Mice 03 medical and health sciences 0302 clinical medicine Mitophagy Autophagy Animals Humans Inner membrane Disease Inner mitochondrial membrane 030304 developmental biology 0303 health sciences Ubiquitination Cytochromes c Cell Biology Cell Death and Autophagy Mitochondria Cell biology Mitochondrial Membranes Mitochondrial fission 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.202006043 |
| Popis: | Oshima et al. report that in the absence of Parkin activity, cells adapt to mitochondrial proteotoxicity through a Drp1-mediated mechanism that includes the severing of the OMM and IMM ubiquitination, followed by recruitment of autophagy machinery to the ubiquitinated IMM proteins. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|