PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis
| Autor: | Chiu-Hui Huang, Paul D. Morton, Stuart H. Worley, Mark W. Kankel, Nikolaos Giagtzoglou, Anindya Sen, Lina Ni, Shireen A. Sarraf, Dionisia P. Sideris, Samuel C. Nussenzweig, Spyros Artavanis-Tsakonas, Lauren Bochicchio, Alicia M. Pickrell, Richard J. Youle |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Mitosis Cellular homeostasis PINK1 Protein Serine-Threonine Kinases Article General Biochemistry Genetics and Molecular Biology Parkin 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Mitophagy Autophagy Homeostasis Humans lcsh:QH301-705.5 Cell Proliferation Chemistry Cell Cycle Cell cycle HCT116 Cells Mitochondria nervous system diseases Cell biology HEK293 Cells 030104 developmental biology lcsh:Biology (General) Centrosome Protein Kinases 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Cell reports Cell Reports, Vol 29, Iss 1, Pp 225-235.e5 (2019) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY PINK1 and Parkin are established mediators of mitophagy, the selective removal of damaged mitochondria by autophagy. PINK1 and Parkin have been proposed to act as tumor suppressors, as loss-of-function mutations are correlated with enhanced tumorigenesis. However, it is unclear how PINK1 and Parkin act in coordination during mitophagy to influence the cell cycle. Here we show that PINK1 and Parkin genetically interact with proteins involved in cell cycle regulation, and loss of PINK1 and Parkin accelerates cell growth. PINK1- and Parkin-mediated activation of TBK1 at the mitochondria during mitophagy leads to a block in mitosis due to the sequestration of TBK1 from its physiological role at centrosomes during mitosis. Our study supports a diverse role for the far-reaching, regulatory effects of mitochondrial quality control in cellular homeostasis and demonstrates that the PINK1/Parkin pathway genetically interacts with the cell cycle, providing a framework for understanding the molecular basis linking PINK1 and Parkin to mitosis. Graphical Abstract In Brief Sarraf et al. use mouse and fly genetics to discover that PINK1 and Parkin influence cell cycle progression. Mitophagy and mitosis independently activate TBK1 at damaged mitochondria and centrosomes, respectively, influencing whether the cell will address mitochondrial quality control or progress with proliferation. |
| Databáze: | OpenAIRE |
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