Unknown

Dataset Information

0

HUWE1 controls MCL1 stability to unleash AMBRA1-induced mitophagy.


ABSTRACT: 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.

SUBMITTER: Strappazzon F 

PROVIDER: S-EPMC7206129 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC6138665 | biostudies-literature
| S-EPMC4904902 | biostudies-other
| S-EPMC10424871 | biostudies-literature
| S-EPMC8621139 | biostudies-literature
| S-EPMC6623066 | biostudies-literature
| S-EPMC9434724 | biostudies-literature
| S-EPMC5932353 | biostudies-literature
| S-EPMC4326570 | biostudies-literature
| S-EPMC3094111 | biostudies-literature
| S-EPMC8246597 | biostudies-literature