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 HUWE1dependent 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.

Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model

“…We also noticed that MCL-1 is reported to act as a suppressor of AMBRA1 to suppress mitophagy, under the conditions of FCCP or CCCP treatment 38 . It is reported that AMBRA1-mediated mitophagy is regulated by HUWE1, an E3 ubiquitin ligase, which could control mitochondrial protein ubiquitylation in cooperation with AMBRA1 during the mitophagy process in a PARKIN-free cellular system, in the condition of MMP deprivation 39 .…”

“…It is reported that AMBRA1mediated mitophagy is regulated by HUWE1, an E3 ubiquitin ligase, which could control mitochondrial protein ubiquitylation in cooperation with AMBRA1 during the mitophagy process in a PARKIN-free cellular system, in the condition of MMP deprivation 39 . And MCL-1 overexpression is sufficient to inhibit recruitment to mitochondria of HUWE1, upon AMBRA1mediated mitophagy induction 38 . However, PINK1/PARKIN, but not HUWE1/AMBRA1, is the main pathway regulating mitophagy in cells with PARKIN, following MMP deprivation, during which the inhibition of MCL-1 on HUWE1 translocation to mitochondria may not inhibit mitophagy.…”

Mitophagy: An Emerging Role in Aging and Age-Associated Diseases

“…During recent years with increasing interest in the exploration of mitophagy, additional mitophagy receptors have been identified to mediate mitophagy including autophagy and beclin 1 regulator 1 (AMBRA1), which acts in a PARKIN-and p62independent manner (Di Rita et al, 2018;Strappazzon et al, 2019), FK506 binding protein 8 (FKBP8) that specifically interacts with microtubule associated protein 1 light chain 3 alpha (MAP1LC3A better known as LC3A) and thus facilitates mitophagy (Bhujabal et al, 2017), and NLR family member X1 (NLRX1) which contains an LIR domain and is harnessed by Listeria during infection to induce mitophagy for its survival in macrophages . Interestingly, upon mitochondrial depolarization, 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) and NIPSNAP2 translocate from the mitochondrial matrix to the surface of the organelle and recruit autophagy receptors and ATG8 proteins for mitophagy.…”

New Aspects of HECT-E3 Ligases in Cell Senescence and Cell Death of Plants

“…Meanwhile, HUWE1 can be located at the mitochondria by interacting with AMBRA1. HUWE1 can also interact with MCL1, which is a potent inhibitor of AMBRA1-mediated mitophagy, for ubiquitination and degradation, which are then involved in mitochondria quality control [51]. These actions demonstrate HECT E3s HUWE1 plays an important role in maintaining the normality of mitochondria.…”

“…The clearance of chloroplast or mitochondrion. Mammalian HECT E3s are involved in maintaining the balance of mitochondria [48,49,50,51] by coordinating with autophagy and unfolding protein. UPL1/2/4/5 are predicted to dually locate in cytoplasm and mitochondrion or plastid, which may involve the clearance of the chloroplast or mitochondrion.…”