2. Academic Validation
  3. Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration

Visualizing and Modulating Mitophagy for Therapeutic Studies of Neurodegeneration

  • Cell. 2020 May 28;181(5):1176-1187.e16. doi: 10.1016/j.cell.2020.04.025.
Hiroyuki Katayama 1,  Hiroshi Hama 1,  Koji Nagasawa 2,  Hiroshi Kurokawa 1,  Mayu Sugiyama 1,  Ryoko Ando 1,  Masaaki Funata 2,  Nobuyo Yoshida 3,  Misaki Homma 4,  Takanori Nishimura 2,  Megumu Takahashi 5,  Yoko Ishida 5,  Hiroyuki Hioki 5,  Yoshiyuki Tsujihata 6,  Atsushi Miyawaki 7
Affiliations

Affiliations

  • 1 Laboratory for Cell Function Dynamics, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-City, Saitama 351-0198, Japan.
  • 2 Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
  • 4 Drug Discovery Chemistry Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
  • 5 Department of Cell Biology and Neuroscience, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan.
  • 6 Innovative Biology Laboratories, Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yoshiyuki.tsujihata@takeda.com.
  • 7 Laboratory for Cell Function Dynamics, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-City, Saitama 351-0198, Japan; Biotechnological Optics Research Team, Center for Advanced Photonics, RIKEN, 2-1 Hirosawa, Wako-City, Saitama 351-0198, Japan. Electronic address: atsushi.miyawaki@riken.jp.
PMID: 32437660 DOI: 10.1016/j.cell.2020.04.025
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.

Keywords

FRET; Parkinsons disease; autophagy; fluorescent protein; high-throughput screening; lysosome; mitochondria; mitophagy.

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