Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1

Igarashi, Ryoko; Yamashita, Shunichi; Yamashita, Tomohiro; Inoue, Keiichi; Fukuda, Tomoyuki; Fukuchi, Takeo; Kanki, Tomotake

doi:10.1038/s41598-020-58315-w

Cited by 34 publications

(20 citation statements)

References 36 publications

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“…These findings suggest that MITOL ubiquitinates and subsequently degrades Parkin in a proteasome‐dependent manner. To understand whether the ubiquitination of Parkin by MITOL has a functional effect on mitophagy, we performed quantitative analysis of mitophagy using the mitochondria‐localized pH‐dependent fluorescent protein mt‐Keima (Katayama et al , 2011; Yamashita et al , 2016; Igarashi et al , 2020), which exhibits a short excitation in normal conditions (pH 8.0) and shifted to longer excitation wavelengths in mitophagy processes because of the acidic environment of the lysosome (pH 4.5). Flow cytometric analysis indicated that MITOL deletion significantly enhanced mitophagy, which was restored to normal levels by a low expression of MITOL.…”

Section: Resultsmentioning

confidence: 99%

MITOL promotes cell survival by degrading Parkin during mitophagy

et al. 2021

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Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin‐mediated cell death through the FKBP38‐dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine‐tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin‐induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.

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Section: Resultsmentioning

confidence: 99%

MITOL promotes cell survival by degrading Parkin during mitophagy

et al. 2021

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“…One compound, the anticancer drug gemcitabine, was identified as inducing mitophagy independent of Parkin ( Table 1 ) but dependent on MUL1. Gemcitabine caused the stabilization of PINK1 without reducing mitochondrial membrane potential ( 136 ).…”

Section: Pharmacological Enhancement Of Mitophagy: From Tool Moleculementioning

confidence: 99%

Targeting mitophagy in Parkinson's disease

Clark

Torre

Hoshikawa

et al. 2021

Journal of Biological Chemistry

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The genetics and pathophysiology of Parkinson’s disease (PD) strongly implicate mitochondria in disease aetiology. Elegant studies over the last two decades have elucidated complex molecular signaling governing the identification and removal of dysfunctional mitochondria from the cell, a process of mitochondrial quality control known as mitophagy. Mitochondrial deficits and specifically reduced mitophagy are evident in both sporadic and familial PD. Mendelian genetics attributes loss-of-function mutations in key mitophagy regulators PINK1 and Parkin to early-onset PD. Pharmacologically enhancing mitophagy and accelerating the removal of damaged mitochondria are of interest for developing a disease-modifying PD therapeutic. However, despite significant understanding of both PINK1-Parkin-dependent and -independent mitochondrial quality control pathways, the therapeutic potential of targeting mitophagy remains to be fully explored. Here, we provide a summary of the genetic evidence supporting the role for mitophagy failure as a pathogenic mechanism in PD. We assess the tractability of mitophagy pathways and prospects for drug discovery and consider intervention points for mitophagy enhancement. We explore the numerous hit molecules beginning to emerge from high-content/high-throughput screening as well as the biochemical and phenotypic assays that enabled these screens. The chemical and biological properties of these reference compounds suggest many could be used to interrogate and perturb mitochondrial biology to validate promising drug targets. Finally, we address key considerations and challenges in achieving preclinical proof-of-concept, including in vivo mitophagy reporter methodologies and disease models, as well as patient stratification and biomarker development for mitochondrial forms of the disease.

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“…To reconcile these conflicting findings, we have to consider functional redundancy of other mitochondrial E3 ligases. Indeed, ARIH1/HHARI (Villa et al , 2017), March5 (Chen et al , 2017), MAPL/MULAN/GIDE/MUL1 (Ambivero et al , 2014; Yun et al , 2014; Li et al , 2015; Igarashi et al , 2020), p62‐keap1‐Rbx1 axis (Yamada et al , 2018), and HUWE1 (Di Rita et al , 2018) have been reported to mediate Parkin‐independent mitophagy. These E3s could compensate for PINK1/Parkin‐mediated mitophagy and conceal the output when the PINK1/Parkin function is inhibited.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms and physiological functions of mitophagy

et al. 2021

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Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.

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Gemcitabine induces Parkin-independent mitophagy through mitochondrial-resident E3 ligase MUL1-mediated stabilization of PINK1

Cited by 34 publications

References 36 publications

MITOL promotes cell survival by degrading Parkin during mitophagy

MITOL promotes cell survival by degrading Parkin during mitophagy

Targeting mitophagy in Parkinson's disease

Molecular mechanisms and physiological functions of mitophagy

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