PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

EMBO Reports - Tập 25 Số 8 - Trang 3324-3347
Giang Nguyen1,2, Brendan Townsend2, Prajakta Gosavi2, Keri‐Lyn Kozul3,2, Soo Siang Ooi2, Denaye Eldershaw4, Saroja Weeratunga4, Meihan Liu4, Mathew V. Jones5,6, S. Sean Millard2, Dominic C.H. Ng2, Michele Pagano7,8,9, Alexis Bonfim‐Melo6, Tobias Schneider10,11, David Komander10,11, Michael Lazarou12,10,11, Brett M. Collins13, Julia K. Pagan14
1Department of Biotechnology, School of Biotechnology, Viet Nam National University-International University, Ho Chi Minh City, Vietnam.
2Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.
3Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, MO, 63110, St Louis, USA.
4The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD 4072, Australia
5School of Chemistry & Molecular Biosciences, University of Queensland, Brisbane, QLD, 4072, Australia.
6The University of Queensland Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia
7Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
8Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, NY, 10065, USA.
9Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, 10016, USA
10Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3068, Australia.
11Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
12Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3068, Australia.
13The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, 4072, Australia. [email protected].
14Faculty of Medicine, School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia. [email protected].

Tóm tắt

Abstract

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 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 SCFFBXL4-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.

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EMBO Reports

Tập 25 Số 8

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