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

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCF ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a cons...

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Published in:EMBO reports 2024-08, Vol.25 (8), p.3324
Main Authors: Nguyen-Dien, Giang Thanh, Townsend, Brendan, Kulkarni, Prajakta Gosavi, Kozul, Keri-Lyn, Ooi, Soo Siang, Eldershaw, Denaye N, Weeratunga, Saroja, Liu, Meihan, Jones, Mathew Jk, Millard, S Sean, Ng, Dominic Ch, Pagano, Michele, Bonfim-Melo, Alexis, Schneider, Tobias, Komander, David, Lazarou, Michael, Collins, Brett M, Pagan, Julia K
Format: Article
Language:English
Subjects:
Animals
F-Box Proteins - genetics
F-Box Proteins - metabolism
HEK293 Cells
HeLa Cells
Humans
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mitochondria - metabolism
Mitochondrial Membranes - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Mitophagy
Phosphoprotein Phosphatases - genetics
Phosphoprotein Phosphatases - metabolism
Protein Binding
Proteolysis
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
SKP Cullin F-Box Protein Ligases - genetics
SKP Cullin F-Box Protein Ligases - metabolism
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Ubiquitin-Protein Ligases
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Summary:Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCF 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 -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.
ISSN:1469-3178