MitoTimer-based high-content screen identifies two chemically-related benzothiophene derivatives that enhance basal mitophagy

Fernanda M. Cerqueira, Noga Kozer, Anton Petcherski, Boris M. Baranovski, Dane Wolf, Essam A. Assali, Yaelle Roth, Roi Gazit, Haim Barr, Eli C. Lewis, Guy Las, Orian S. Shirihai

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Mitochondrial turnover is required for proper cellular function. Both mitochondrial biogenesis and mitophagy are impaired in several degenerative and age-related diseases. The search for mitophagy activators recently emerged as a new therapeutical approach; however, there is a lack in suitable tools to follow mitochondrial turnover in a high-throughput manner. We demonstrate that the fluorescent protein, MitoTimer, is a reliable and robust probe to follow mitochondrial turnover. The screening of 15 000 small molecules led us to two chemically-related benzothiophenes that stimulate basal mitophagy in the beta-cell line, INS1. Enhancing basal mitophagy was associated with improved mitochondrial function, higher Complex I activity and Complex II and III expressions in INS1 cells, as well as better insulin secretion performance in mouse islets. The possibility of further enhancing mitophagy in the absence of mitochondrial stressors points to the existence of a 'basal mitophagy spare capacity'. To this end, we found two small molecules that can be used as models to better understand the physiological regulation of mitophagy.

Original languageEnglish
Pages (from-to)461-475
Number of pages15
JournalBiochemical Journal
Volume477
Issue number2
DOIs
StatePublished - 31 Jan 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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