Ubiquitination of ABCE1 by NOT4 in Response to Mitochondrial Damage Links Co-translational Quality Control to PINK1-Directed Mitophagy

Wu, Zhihao; Wang, Yan; Lim, Junghyun; Liu, Boxiang; Li, Yanping; Vartak, Rasika; Stankiewicz, Trisha R.; Montgomery, Stephen B.; Lu, Bingwei

doi:10.1016/j.cmet.2018.05.007

Cited by 71 publications

(82 citation statements)

References 68 publications

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“…Our recent studies revealed that on damaged mitochondria, the recruitment of cotranslational quality control factors Pelo, ABCE1, and NOT4 to stalled ribosomes results in NOT4‐mediated polyubiquitination of ABCE1 and that polyubiquitinated ABCE1 (poly‐Ub‐ABCE1) provides a molecular signal for recruiting autophagy receptors to initiate mitophagy . We provided evidence supporting that the PINK1 pathway is deployed to stimulate translation of nuclear‐encoded respiratory chain (nRCC) mRNAs on mildly damaged mitochondria to promote RC biogenesis and thus mitochondrial repair, revealing a new physiological role of PINK1/Parkin in mitochondrial regulation.…”

Section: Mitophagy and Neurodegenerative Diseasesmentioning

confidence: 85%

“…(poly-Ub-ABCE1) provides a molecular signal for recruiting autophagy receptors to initiate mitophagy. 119 We provided evidence supporting that the PINK1 pathway is deployed to stimulate translation of nuclear-encoded respiratory chain (nRCC) mRNAs on mildly damaged mitochondria to promote RC biogenesis and thus mitochondrial repair, revealing a new physiological role of PINK1/ Parkin in mitochondrial regulation. However, for severely damaged mitochondria that are beyond repair, the PINK1 pathway is used to direct their clearance by mitophagy.…”

Section: Pink1 and Parkinmentioning

confidence: 90%

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Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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Section: Mitophagy and Neurodegenerative Diseasesmentioning

confidence: 85%

Section: Pink1 and Parkinmentioning

confidence: 90%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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“…Remarkably, OE of co-translational QC factors, with the OE effect verified for certain key factors ( Figure S2D), effectively rescued PINK1 phenotypes in the muscle (Figure 2E Consistent with the co-translational QC genes working in the same pathway as PINK1 to control C-I30-u expression and mitochondrial function, muscle-specific knockdown of UPF3, a key NMD factor (Leeds et al, 1992), was sufficient to phenocopy PINK1. Similarly, musclespecific expression of dominant-negative VCP, a key RQC factor (Brandman et al, 2012), or overexpression of NOT4, a protein implicated in the co-translational QC of C-I30 (Wu et al, 2018), also phenocopied PINK1 ( Figure 1F; S1B, C).…”

Section: Co-translational Qc Pathways Regulate C-i30-u Formationmentioning

confidence: 88%

“…ABCE1 may be part of the translation machinery that senses mitochondrial health. Indeed, metazoan ABCE1 is ubiquitinated under mitochondrial stress (Wu et al, 2018), and at least in yeast cells, WT level of ABCE1 is below the threshold sufficient for complete ribosome recycling (Young et al, 2015). ABCE1 is innately metastable and prone to sequestration by disease-associated aggregates (Olzscha et al, 2011).…”

Section: Linking Mitochondrial Dysfunction With Cte-induced Neurodegementioning

confidence: 99%

MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure

Tantray

Lim

et al. 2019

Preprint

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Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here we describe a phenomenon termed MISTERMINATE (mitochondrial stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs including complex-I 30kD subunit (C-I30) mRNA, occurring on mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C-terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally-extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE. translation, attenuated disease progression (Johnson et al., 2013). These studies strongly support an intimate connection between mitochondria and cytosolic translation, although the underlying mechanism is poorly defined.Here we provide a molecular link between mitochondrial function and cytosolic translation/proteostatsis. Mitochondrial damage induces translational stalling of mitochondrial outer membrane (MOM)-associated C-I30 mRNA by impairing the termination and ribosomerecycling factors eRF1 and ABCE1. Stalled ribosomes continue to add certain AAs to the Cterminus of C-I30, in a process analogous to CAT-tailing but with distinct features. C-I30 with C-terminal extension (CTE) inhibits oxidative phosphorylation (OxPhos) when assembled into C-I, and disrupts proteostasis when aggregating in the cytosol. Genetic manipulations of eRF1, ABCE1, or conserved CAT-tailing machinery prevent C-I30 CTE formation and rescue neuromuscular degeneration in PINK1 flies. PINK1/Parkin mechanistically regulates the RQC and CTE processes. These results identify C-I30 and possibly ATP5a as the first endogenous metazoan substrates of the CTE process, revealing intimate connections between mitochondrial health, co-translational QC, and proteostasis in neuromuscular tissues. RESULTS A Novel Form of C-I30 in PINK1 Neuromuscular TissuesHuman C-I is the largest enzyme of the respiratory chain, comprising 45 nuclear-or mitochondrial-encoded subunits, with C-I30 being part of the core assembly (Formosa et al., 2018). Mutations in C-I30 cause OxPhos and neuromuscular defects in Leigh syndrome. C-I30mRNA is translationally repressed in the cytosol before being recruited to MOM and reactivated by PINK1 and Parkin (Gehrke et al., 2015), two factors linked to familial PD.In muscle and brain tissues of PINK1 flies, we detected canonical C-I30...

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“…The cotranslational quality control factors Pelo, ABCE1, and NOT4 are recruited to the mRNA‐ribonucleoprotein complex, and ABCE1 is ubiquitinated by NOT4. As a result, the poly‐Ub‐ABCE1 recruits the autophagy receptors such as p62, PTEN, and NDP52 to initiate mitophagy . In this issue, Yan Wang and Na Liu at Soochow University and Bingwei Lu reviewed the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases .…”

mentioning

confidence: 99%