Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration.
Cell
; 181(5): 1176-1187.e16, 2020 05 28.
Article
in En
| MEDLINE
| ID: mdl-32437660
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fluorescence Resonance Energy Transfer
/
Mitophagy
/
Lysosomes
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cell
Year:
2020
Type:
Article
Affiliation country:
Japan