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FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for

Alvaro Sanchez-Martinez1, Aitor Martinez1, Alexander J Whitworth1

  • 1MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.

Plos Biology
|August 3, 2023
PubMed

Insights

FBXO7/ntc regulates mitochondrial homeostasis and mitophagy independently of Pink1 and Parkin. This protein works with USP30 to control mitochondrial quality, offering new therapeutic targets for Parkinson

Area of Science:

  • Molecular Biology
  • Genetics
  • Neuroscience

Background:

  • Parkinson's disease (PD) pathogenesis involves genes linked to heritable forms.
  • FBXO7 mutations cause autosomal recessive PD and regulate mitochondrial homeostasis.
  • Understanding FBXO7's role in mitophagy is crucial for PD research.

Purpose of the Study:

  • To investigate functional homology between human FBXO7 and its Drosophila orthologue, ntc.
  • To explore the role of ntc in mitophagy in vivo.
  • To elucidate the mechanism by which ntc modulates mitochondrial quality control.

Main Methods:

  • Analysis of ntc mutants in Drosophila.
  • Assessment of ntc's effect on mitophagy pathways.
  • Investigation of interactions between ntc, USP30, Pink1, and Parkin.

Main Results:

  • ntc mutants partially phenocopy Pink1 and Parkin mutants in Drosophila.
  • ntc overexpression suppresses Parkin phenotypes.
  • ntc promotes basal mitophagy via Pink1/Parkin-independent ubiquitination of mitochondrial proteins, opposed by USP30.

Conclusions:

  • FBXO7/ntc acts in equilibrium with USP30 to maintain basal mitochondrial quality control.
  • This mechanism provides a checkpoint for mitochondrial homeostasis in vivo.
  • FBXO7/ntc represents a potential therapeutic target for Parkinson's disease.

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