Endosomal-associated RFFL facilitates mitochondrial clearance by enhancing PRKN/parkin recruitment to mitochondria

Mutations in the ubiquitin ligase PRKN (parkin RBR E3 ubiquitin protein ligase) are associated with Parkinson disease and defective mitophagy. Conceptually, PRKN-dependent mitophagy is classified into two phases: 1. PRKN recruits to and ubiquitinates mitochondrial proteins; 2. formation of phagophor...

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Bibliographic Details
Published inAutophagy Vol. 18; no. 12; pp. 2851 - 2864
Main Authors Ravindran, Rishith, Velikkakath, Anoop Kumar G., Narendradev, Nikhil Dev, Chandrasekharan, Aneesh, Santhoshkumar, T. R., Srinivasula, Srinivasa M.
Format Journal Article
LanguageEnglish
Published United States Taylor & Francis 01.12.2022
Subjects
Autophagy
Brief Report
Endosomes - metabolism
Mitochondria - metabolism
Protein Kinases - metabolism
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - metabolism
PRKN
mitophagy
ubiquitin ligases
RFFL
Endosomes
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ISSN1554-8627
1554-8635
1554-8635
DOI10.1080/15548627.2022.2052460

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Summary:Mutations in the ubiquitin ligase PRKN (parkin RBR E3 ubiquitin protein ligase) are associated with Parkinson disease and defective mitophagy. Conceptually, PRKN-dependent mitophagy is classified into two phases: 1. PRKN recruits to and ubiquitinates mitochondrial proteins; 2. formation of phagophore membrane, sequestering mitochondria for degradation. Recently, endosomal machineries are reported to contribute to the later stage for membrane assembly. We reported a role for endosomes in the events upstream of phase 1. We demonstrate that the endosomal ubiquitin ligase RFFL (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) associated with damaged mitochondria, and this association preceded that of PRKN. RFFL interacted with PRKN, and stable recruitment of PRKN to damaged mitochondria was substantially reduced in KO cells. Our study unraveled a novel role of endosomes in modulating upstream pathways of PRKN-dependent mitophagy initiation. CCCP: carbonyl cyanide 3-chlorophenylhydrazone; DMSO: dimethyl sulfoxide; EGFP: enhanced green fluorescence protein; KO: knockout; PRKN: parkin RBR E3 ubiquitin protein ligase; RFFL: ring finger and FYVE like domain containing E3 ubiquitin protein ligase; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; WT: wild-type.
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These authors contributed equally to this work.
ISSN:1554-8627
1554-8635
1554-8635
DOI:10.1080/15548627.2022.2052460