Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration
| Autor: | Hiroshi Hama, Yoko Ishida, Mayu Sugiyama, Hiroyuki Hioki, Hiroyuki Katayama, Yoshiyuki Tsujihata, Masaaki Funata, Koji Nagasawa, Megumu Takahashi, Ryoko Ando, Takanori Nishimura, Nobuyo Yoshida, Misaki Homma, Hiroshi Kurokawa, Atsushi Miyawaki |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Neurodegeneration Autophagy Mitochondrion Biology medicine.disease General Biochemistry Genetics and Molecular Biology Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Lysosome Mitochondrial targeting Mitophagy medicine Fluorescent protein 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Cell. 181:1176-1187.e16 |
| ISSN: | 0092-8674 |
| Popis: | Dysfunctional mitochondria accumulate in many human diseases. Accordingly, mitophagy, which removes these mitochondria through lysosomal degradation, is attracting broad attention. Due to uncertainties in the operational principles of conventional mitophagy probes, however, the specificity and quantitativeness of their readouts are disputable. Thorough investigation of the behaviors and fates of fluorescent proteins inside and outside lysosomes enabled us to develop an indicator for mitophagy, mito-SRAI. Through strict control of its mitochondrial targeting, we were able to monitor mitophagy in fixed biological samples more reproducibly than before. Large-scale image-based high-throughput screening led to the discovery of a hit compound that induces selective mitophagy of damaged mitochondria. In a mouse model of Parkinsons disease, we found that dopaminergic neurons selectively failed to execute mitophagy that promoted their survival within lesions. These results show that mito-SRAI is an essential tool for quantitative studies of mitochondrial quality control. |
| Databáze: | OpenAIRE |
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