PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCF FBXL4 .

Autor:	Nguyen-Dien GT; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.; Department of Biotechnology, School of Biotechnology, Viet Nam National University-International University, Ho Chi Minh City, Vietnam., Townsend B; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia., Kulkarni PG; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia., Kozul KL; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, MO, 63110, St Louis, USA., Ooi SS; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia., Eldershaw DN; The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, 4072, Australia., Weeratunga S; The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, 4072, Australia., Liu M; The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, 4072, Australia., Jones MJ; The University of Queensland Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4102, Australia.; School of Chemistry & Molecular Biosciences, University of Queensland, Brisbane, QLD, 4072, Australia., Millard SS; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia., Ng DC; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia., Pagano M; Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY, 10065, USA., Bonfim-Melo A; The University of Queensland Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4102, Australia., Schneider T; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3068, Australia., Komander D; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3068, Australia., Lazarou M; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3068, Australia.; Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3068, Australia.; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Collins BM; The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, 4072, Australia. b.collins@imb.uq.edu.au., Pagan JK; Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia. j.pagan@uq.edu.au.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2024 Aug; Vol. 25 (8), pp. 3324-3347. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1038/s44319-024-00181-y
Abstrakt:	Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCF FBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCF FBXL4 -mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy. (© 2024. The Author(s).)
Databáze:	MEDLINE
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