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Dual Perturbation of Electron Transport Chain (ETC) Complex and ATP Synthase Triggers PINK1/Parkin‐dependent Mitophagy
Author(s) -
Ramirez Adrian Thomas,
Liu Xuedong
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.543.9
Subject(s) - parkin , pink1 , mitophagy , mitochondrion , microbiology and biotechnology , parkinson's disease , biology , chemistry , biochemistry , disease , medicine , autophagy , apoptosis
Neurodegenerative disorders like Parkinson's Disease arise in part due to accumulation of unhealthy mitochondria. PINK1 and Parkin, found to be deficient in some Familial Parkinson's Disease patients, are known to orchestrate mitochondrial quality control responses like mitophagy. Research into PINK1 and Parkin function has been focused primarily on downstream signaling events, but the exact type of damage signals originating from defected mitochondria to trigger PINK1 stabilization and subsequent Parkin recruitment to the outer membrane of damaged mitochondria remains elusive. We propose PINK1 and Parkin act in tandem to monitor the integrity and activity of ETC complexes and ATP synthase to ensure robust energy production. To test this hypothesis, we profiled several small molecule inhibitors with well‐documented inhibitory activities towards ETC complexes for their effects on PINK1 and Parkin activation. We found that while dual inhibition of complex III and V results in robust Parkin recruitment to damaged mitochondria and mitophagy responses, dual inhibition of complex I and V has only modest effect and other combinations have no effect. PINK1 and Parkin activation as a result of dual assault of ETC complexes can be phenocopied with perturbations of these complexes with siRNA. Thus, our study supports the idea that PINK1 and Parkin are guardians of ETC quality and status. Damaged mitochondria as a result of specific defects in oxidative phosphorylation can be cleared by PINK1 and Parkin dependent mitophagy. This mechanism could be relevant in understanding their dysregulation in Parkinson's Disease. Support or Funding Information National Institute of General Medical Sciences R01 GM113141, National Institute of General Medical Sciences T32GM08759, S10 RR026680 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .