HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

Rita, Anthea Di; Peschiaroli, Angelo; Dâ2Acunzo, Pasquale; Strobbe, Daniela; Hu, Zehan; Gruber, Jens; Nygaard, Mads; Lambrughi, Matteo; Melino, Gerry; Papaleo, Elena; Dengjel, Jörn; Alaoui, Saı̈d El; Campanella, Michelangelo; Dötsch, Volker; Rogov, Vladimir V.; Strappazzon, Flavie; Cecconi, Francesco

doi:10.1038/s41467-018-05722-3

Cited by 217 publications

(213 citation statements)

References 71 publications

(109 reference statements)

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“…By supporting the high bioenergetic demand of cancer cells, mitophagy sustains tumor growth. HUWE1 may influence cancer metabolism and tumor progression by promoting mitophagy through MFN2 ubiquitylation (Di Rita et al, 2018). The role of HUWE1 in tumorigenesis has been very debated.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that the dual role of HUWE1 in cancer is influenced by different protein adaptors or post-translational modifications. In this respect, AMBRA1 acts as a cofactor for HUWE1 to favor mitophagy induction (Di Rita et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…This modification increases binding of AMBRA1 to LC3B and thus fosters its mitophagy receptor function. Notably, HUWE1 potentiates AMBRA1‐activated phosphorylation state, thus establishing a functional crosstalk between HUWE1 and AMBRA1 in mitophagy regulation (Di Rita et al ., ).…”

Section: Hect‐type E3s In Autophagy Regulationmentioning

confidence: 97%

“…They function as receptors for ubiquitin-modified cargoes interacting with ubiquitin or polyubiquitin chains via the UBA domain, and then, autophagy adaptors deliver ubiquitylated cargoes to the autophagosome via the LIR domain (Pankiv et al, 2007). During mitophagy, a clearance system for removal of damaged mitochondria through the autophagosome-lysosome pathway, recognition of ubiquitin-modified substrates is mainly mediated by the optineurin (OPTN), NDP52 and AMBRA1 receptors (Di Rita et al, 2018;Heo et al, 2015;Yamano et al, 2016). By acting as bridges between ubiquitin-tagged mitochondria and LC3, they allow mitochondria delivery to autophagosomes.…”

Section: Autophagymentioning

confidence: 99%

“…HUWE1 has been also implicated in mitophagy regulation (Di Rita et al, 2018). During mitophagy, ubiquitylation is a key process that contributes to normal turnover of mitochondrial proteins.…”

Section: Huwe1mentioning

confidence: 99%

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Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

et al. 2019

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Autophagy is a conserved self‐eating process that delivers cytoplasmic material to the lysosome to allow degradation of intracellular components, including soluble, unfolded and aggregated proteins, damaged organelles, and invading microorganisms. Autophagy provides a homeostatic control mechanism and is essential for balancing sources of energy in response to nutrient stress. Autophagic dysfunction or dysregulation has been implicated in several human pathologies, including cancer and neurodegeneration, and its modulation has substantial potential as a therapeutic strategy. Given the relevant clinical and therapeutic implications of autophagy, there is emerging intense interest in the identification of the key factors regulating the components of the autophagic machinery. Various post‐translational modifications, including ubiquitylation, have been implicated in autophagy control. The list of the E3 ubiquitin protein ligases involved in the regulation of several steps of the autophagic process is continuously growing. In this review, we will focus on recent advances in the understanding of the role of the homologous to the E6AP carboxyl terminus‐type E3 ubiquitin ligases in autophagy control.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hect‐type E3s In Autophagy Regulationmentioning

confidence: 97%

Section: Autophagymentioning

confidence: 99%

Section: Huwe1mentioning

confidence: 99%

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Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

et al. 2019

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Mitochondrial turnover and homeostasis in ageing and neurodegeneration

Markaki

Tavernarakis

2020

FEBS Letters

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Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, genetic and extrinsic factors influence senescent decline and ageing. Numerous gene mutations and treatments have been shown to extend the lifespan of organisms ranging from the unicellular Saccharomyces cerevisiae to primates. Most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to counter both intrinsic stress and extrinsic stress. Mitochondria, the main energy hub of the cell, are highly dynamic organelles, playing essential roles in cell physiology. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, survival and healthspan. Maintenance of mitochondrial function and energy homeostasis requires both generation of new healthy mitochondria and elimination of the dysfunctional ones. Here, we survey the mechanisms regulating mitochondrial number in cells, with particular emphasis on neurons. We, further, discuss recent findings implicating perturbation of mitochondrial homeostasis in cellular senescence and organismal ageing as well as in age-associated neurodegenerative diseases.

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Mitochondrial clearance: mechanisms and roles in cellular fitness

Onishi

Okamoto

2021

FEBS Letters

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Edited by Agnieszka ChacinskaMitophagy is one of the selective autophagy pathways that catabolizes dysfunctional or superfluous mitochondria. Under mitophagy-inducing conditions, mitochondria are labeled with specific molecular landmarks that recruit the autophagy machinery to the surface of mitochondria, enclosed into autophagosomes, and delivered to lysosomes (vacuoles in yeast) for degradation. As damaged mitochondria are the major sources of reactive oxygen species, mitophagy is critical for mitochondrial quality control and cellular health. Moreover, appropriate control of mitochondrial quantity via mitophagy is vital for the energy supply-demand balance in cells and whole organisms, cell differentiation, and developmental programs. Thus, it seems conceivable that defects in mitophagy could elicit pleiotropic pathologies such as excess inflammation, tissue injury, neurodegeneration, and aging. In this review, we will focus on the molecular basis and physiological relevance of mitophagy, and potential of mitophagy as a therapeutic target to overcome such disorders.

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HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα

Cited by 217 publications

References 71 publications

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

Mitochondrial turnover and homeostasis in ageing and neurodegeneration

Mitochondrial clearance: mechanisms and roles in cellular fitness

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