title: SREBF1 links lipogenesis to mitophagy and sporadic Parkinson disease.
abstract: Mitochondrial quality control has an impact on many diseases, but intense research has focused on the action of 2 genes linked to heritable forms of Parkinson disease (PD), PINK1 and PARK2/parkin, which act in a common pathway to promote mitophagy. However, criticism has been raised that little evidence links this mechanism to sporadic PD. To gain a greater insight into the mechanisms of PINK1-PARK2 mediated mitophagy, we undertook a genome-wide RNAi screen in Drosophila and human cell models. Strikingly, we discovered several components of the lipogenesis pathway, including SREBF1, playing a conserved role in mitophagy. Our results suggest that lipids influence the stabilization of PINK1 during the initiation of mitophagy. Importantly, SREBF1 has previously been identified as a risk locus for sporadic PD, and thus implicates aberrant mitophagy as contributing to sporadic PD. Our findings suggest a role for lipid synthesis in PINK1-PARK2 mediated mitophagy, and propose a mechanistic link between familial and sporadic PD, supporting a common etiology.
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics; Sheffield, UK; Department of Biomedical Science; University of Sheffield; Sheffield, UK.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Ivatt
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics; Sheffield, UK; Department of Biomedical Science; University of Sheffield; Sheffield, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whitworth
mesh_terms: D000818:Animals; D004331:Drosophila melanogaster; D004795:Enzyme Stability; D006801:Humans; D050155:Lipogenesis; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D008954:Models, Biological; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D051780:Sterol Regulatory Element Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: Drosophila; FBXW7; Parkin; Parkinson disease; SREBF1; lipids