HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy: Cell Death and Differentiation

F. Strappazzon, A. Di Rita, A. Peschiaroli, P.P. Leoncini, F. Locatelli, G. Melino, F. Cecconi

Research output: Contribution to journalArticlepeer-review


Receptor-mediated mitophagy is a crucial process involved in mitochondria quality control. AMBRA1 is a mitophagy receptor for the selective removal of damaged mitochondria in mammalian cells. A critical unresolved issue is how AMBRA1-mediated mitophagy is controlled in response to cellular stress. Here, we investigated the role of BCL2-family proteins on AMBRA1-dependent mitophagy and showed that MCL1 delays AMBRA1-dependent mitophagy. Indeed, MCL1 overexpression is sufficient to inhibit recruitment to mitochondria of the E3 Ubiquitin ligase HUWE1, a crucial dynamic partner of AMBRA1, upon AMBRA1-mediated mitophagy induction. In addition, we found that during mitophagy induced by AMBRA1, MCL1 levels decreased but were sustained by inhibition of the GSK-3β kinase, which delayed AMBRA1-mediated mitophagy. Also, we showed that MCL1 was phosphorylated by GSK-3β at a conserved GSK-3 phosphorylation site (S159) during AMBRA1-mediated mitophagy and that this event was accompanied by HUWE1-dependent MCL1 degradation. Altogether, our results demonstrate that MCL1 stability is regulated by the kinase GSK-3β and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy. Our work thus defines MCL1 as an upstream stress-sensitive protein, functional in AMBRA1-mediated mitophagy. © 2019, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
Original languageEnglish
Pages (from-to)1155-1168
Number of pages14
JournalCell Death Differ.
Issue number4
Publication statusPublished - 2020


  • AMBRA1 protein
  • E3 ubiquitin ligase HUWE1
  • glycogen synthase kinase 3beta
  • peptides and proteins
  • protein mcl 1
  • ubiquitin protein ligase E3
  • unclassified drug
  • Article
  • CD34 selection
  • cell proliferation
  • controlled study
  • down regulation
  • enzyme inhibition
  • enzyme phosphorylation
  • enzyme regulation
  • human
  • human cell
  • immunocytochemistry
  • mitochondrion
  • mitophagy
  • priority journal
  • protein degradation
  • protein expression
  • protein stability
  • ubiquitination


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