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HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy

Flavie Strappazzon1, Anthea Di Rita2,3, Angelo Peschiaroli4

  • 1IRCCS Fondazione Santa Lucia, 00143, Rome, Italy. f.strappazzon@hsantalucia.it.

Cell Death and Differentiation
|August 23, 2019
PubMed

Insights

MCL1 protein delays mitophagy, a cellular process for removing damaged mitochondria. Its stability is controlled by GSK-3β kinase and HUWE1 ligase, impacting AMBRA1-mediated mitophagy during cellular stress.

Area of Science:

  • Cellular Biology
  • Mitochondrial Dynamics
  • Autophagy and Mitophagy

Background:

  • Receptor-mediated mitophagy is essential for mitochondrial quality control in mammalian cells.
  • AMBRA1 acts as a mitophagy receptor, selectively removing damaged mitochondria.
  • The regulation of AMBRA1-mediated mitophagy under cellular stress remains poorly understood.

Purpose of the Study:

  • To investigate the role of BCL2-family proteins, specifically MCL1, in AMBRA1-dependent mitophagy.
  • To elucidate the molecular mechanisms controlling MCL1 stability and its impact on mitophagy.

Main Methods:

  • Investigated the interaction between MCL1, AMBRA1, HUWE1, and GSK-3β.
  • Utilized overexpression and kinase inhibition strategies to study MCL1's effect on mitophagy.
  • Analyzed MCL1 phosphorylation and degradation during AMBRA1-mediated mitophagy.

Main Results:

  • MCL1 was identified as an inhibitor of AMBRA1-dependent mitophagy.
  • MCL1 overexpression prevented the recruitment of HUWE1 to mitochondria, a key step in mitophagy.
  • MCL1 levels decreased during mitophagy but were stabilized by GSK-3β inhibition, delaying the process.
  • GSK-3β phosphorylated MCL1 at S159, leading to HUWE1-dependent MCL1 degradation.

Conclusions:

  • MCL1 stability is dynamically regulated by the interplay between GSK-3β kinase and HUWE1 E3 ubiquitin ligase.
  • This regulation is critical for controlling AMBRA1-mediated mitophagy in response to cellular stress.
  • MCL1 functions as an upstream, stress-sensitive regulator of AMBRA1-mediated mitophagy.

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