MITOL promotes cell survival by degrading Parkin during mitophagy
Open Access
- 10 February 2021
- journal article
- research article
- Published by EMBO in EMBO Reports
- Vol. 22 (3), e49097
- https://doi.org/10.15252/embr.201949097
Abstract
Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin‐mediated cell death through the FKBP38‐dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine‐tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin‐induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.Keywords
Funding Information
- Japan Society for the Promotion of Science (15H01190, 17H04053, 18H04869, 20H03454, 20H04911, 16K08246)
- Ministry of Education, Culture, Sports, Science and Technology (S1411014)
- Japan Agency for Medical Research and Development (JP17gm5010002, JP18gm5010002, JP19gm5010002, JP20gm5010002)
- Takeda Science Foundation
- Sumitomo Foundation
- Cosmetology Research Foundation
- Ono Medical Research Foundation
- Tokyo Biochemical Research Foundation
This publication has 61 references indexed in Scilit:
- PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagyScientific Reports, 2012
- Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase ParkinDevelopmental Cell, 2012
- PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondriaNature Communications, 2012
- PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagyThe Journal of cell biology, 2010
- PINK1-dependent recruitment of Parkin to mitochondria in mitophagyProceedings of the National Academy of Sciences of the United States of America, 2009
- Mitochondrial Ubiquitin Ligase MITOL Ubiquitinates Mutant SOD1 and Attenuates Mutant SOD1-induced Reactive Oxygen Species GenerationMolecular Biology of the Cell, 2009
- Identification, analysis, and prediction of protein ubiquitination sitesProteins, 2009
- Mitofusin 2 tethers endoplasmic reticulum to mitochondriaNature, 2008
- Parkin is recruited selectively to impaired mitochondria and promotes their autophagyThe Journal of cell biology, 2008
- A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamicsThe EMBO Journal, 2006