Arrested PPTC7 import couples mitochondrial depolarisation to NIX and BNIP3 degradation
- 1University of Liverpool
Abstract
Mitophagy is initiated by two distinct pathways that are both coupled to mitochondrial protein import. Import stress stabilises PINK1 at the outer mitochondrial membrane, activating the Parkin and ubiquitin-dependent pathway. Receptor-mediated pathways are governed by the expression of outer mitochondrial membrane proteins NIX and BNIP3. Mitophagy is limited by their degradation, via SCFFBXL4. This requires the PP2C-family phosphatase PPTC7 as an obligate substrate recognition factor, captured at the outer membrane en route to the matrix. We show that mitochondrial depolarisation exerts opposing effects on these two pathways. In RPE1 cells, depolarisation drives rapid, ubiquitin and proteasome-dependent loss of NIX and BNIP3 that requires ongoing protein synthesis of PPTC7. Using a doxycycline-mediated pulse-chase assay, we demonstrate directly that depolarisation inhibits import of newly synthesised PPTC7, and that this arrested PPTC7 is itself degraded in an FBXL4-dependent manner alongside its substrates. Thus, import arrest both stabilises PINK1 and eliminates NIX and BNIP3, coordinating a switch between mitophagy pathways, while concurrent degradation of PPTC7 couples mitophagy receptor turnover to PPTC7 synthesis rates.
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BibTeX
@misc{georgiou2026arrested,
title = {{Arrested PPTC7 import couples mitochondrial depolarisation to NIX and BNIP3 degradation}},
author = {I. C. Georgiou and A. Clancy and E. V. Rusilowicz-Jones and S. Urbe and M. Clague},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759620},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759620v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Arrested PPTC7 import couples mitochondrial depolarisation to NIX and BNIP3 degradation
AU - I. C. Georgiou
AU - A. Clancy
AU - E. V. Rusilowicz-Jones
AU - S. Urbe
AU - M. Clague
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759620
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759620v1
AB - Mitophagy is initiated by two distinct pathways that are both coupled to mitochondrial protein import. Import stress stabilises PINK1 at the outer mitochondrial membrane, activating the Parkin and ubiquitin-dependent pathway. Receptor-mediated pathways are governed by the expression of outer mitochondrial membrane proteins NIX and BNIP3. Mitophagy is limited by their degradation, via SCFFBXL4. This requires the PP2C-family phosphatase PPTC7 as an obligate substrate recognition factor, captured at the outer membrane en route to the matrix. We show that mitochondrial depolarisation exerts opposing effects on these two pathways. In RPE1 cells, depolarisation drives rapid, ubiquitin and proteasome-dependent loss of NIX and BNIP3 that requires ongoing protein synthesis of PPTC7. Using a doxycycline-mediated pulse-chase assay, we demonstrate directly that depolarisation inhibits import of newly synthesised PPTC7, and that this arrested PPTC7 is itself degraded in an FBXL4-dependent manner alongside its substrates. Thus, import arrest both stabilises PINK1 and eliminates NIX and BNIP3, coordinating a switch between mitophagy pathways, while concurrent degradation of PPTC7 couples mitophagy receptor turnover to PPTC7 synthesis rates.
ER -