Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy

Li, Jie; Qi, Wei; Guo, Chen; Feng, Du; Liu, Jinhua; Ma, Biao; Zhou, Changqian; Mu, Chenglong; Zhang, Weilin; Chen, Quan; Zhu, Yushan

doi:10.1080/15548627.2015.1017180

Cited by 124 publications

(96 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is not uncommon for an E3 ubiquitin ligase to be multifunctional and have different substrates. For example, MAPL itself has several known substrate proteins in different physiological processes, including the mitochondrial and peroxisomal fission factor dynaminrelated protein DRP1 (Braschi et al, 2009), E3 ubiquitin ligase TRAF2 in mitochondrial hyperfusion (Zemirli et al, 2014), ULK1 in mitophagy (Li et al, 2015), mitofusin in mitochondrial integrity maintenance (Yun et al, 2014), RIG-I in mitochondrial antiviral response (Jenkins et al, 2013), the Ser/Thr kinase Akt in cell proliferation and viability (Bae et al, 2012), and p53 and p73 when they translocate to mitochondria under cell stress (Jung et al, 2011;Min et al, 2015). When we performed a phylogenetic analysis using SP1, its two homologs from Arabidopsis SPL1 and SPL2, and homologous sequences from other eukaryotic species, MAPL was grouped together with SP1 and SPL1 in the same subclade conserved in plants and animals, whereas SPL2 belonged to a plant-specific subclade, suggesting a strong evolutionary relationship between SP1 and MAPL (Pan et al, 2016).…”

mentioning

confidence: 99%

The Arabidopsis E3 Ubiquitin Ligase SP1 Targets to Chloroplasts, Peroxisomes, and Mitochondria

Pan

2018

Plant Physiol.

View full text Add to dashboard Cite

mentioning

confidence: 99%

The Arabidopsis E3 Ubiquitin Ligase SP1 Targets to Chloroplasts, Peroxisomes, and Mitochondria

Pan

2018

Plant Physiol.

View full text Add to dashboard Cite

“…Mitochondrial E3 ubiquitin ligase 1 was originally discovered as an E3 ligase of ubiquitination. It promotes autophagy degradation of mitochondria by interacting with a specific E2 ubiquitination‐binding enzyme and autophagy‐related protein GABARAP, or mediating the ubiquitination of autophagy upstream protein ULK1 . Although Mul1 protein was immediately degraded potentially because of the Mul1‐enhanced autophagy flux, the autophagy flux is actually increased in cells overexpressing Mul1 as confirmed by increased levels of Mul1 mRNA.…”

Section: Discussionmentioning

confidence: 97%

“…9,23 Mitochondrial E3 ubiquitin ligase 1 (Mul1), a multifunctional mitochondrial membrane-associated protein located on the outer membrane of the mitochondrion with two transmembrane domains and one Ring-finger domain, 24 regulates different biological processes such as mitochondrial dynamics, cell growth, apoptosis and mitophagy (autophagy degradation of mitochondria), through ubiquitination and SUMOylation. [25][26][27] Mitophagy and mitochondrial dynamics cause frequent changes in both quantity and morphology of cells and organelles. 28 The imbalance of homeostasis is clearly associated with diseases such as Parkinson's disease, viral infection and carcinomas.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial E3 ubiquitin ligase 1 promotes autophagy flux to suppress the development of clear cell renal cell carcinomas

Yuan

et al. 2019

Cancer Science

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors in the urinary system. Surgical intervention is the preferred treatment for ccRCC, but targeted biological therapy is required for postoperative recurrent or metastatic ccRCC. Autophagy is an intracellular degradation system for misfolded/aggregated proteins and dysfunctional organelles. Defective autophagy is associated with many diseases. Mul1 is a mitochondrion‐associated E3 ubiquitin ligase and involved in the regulation of divergent pathophysiological processes such as mitochondrial dynamics, and thus affects the development of various diseases including cancers. Whether Mul1 regulates ccRCC development and what is the mechanism remain unclear. Histochemical staining and immunoblotting were used to analyze the levels of Mul1 protein in human renal tissues. Statistical analysis of information associated with tissue microarray and The Cancer Genome Atlas (TCGA) database was conducted to show the relationship between Mul1 expression and clinical features and survival of ccRCC patients. Impact of Mul1 on rates of cell growth and migration and autophagy flux were tested in cultured cancer cells. Herein we show that Mul1 promoted autophagy flux to facilitate the degradation of P62‐associated protein aggresomes and adipose differentiation‐related protein (ADFP)‐associated lipid droplets and suppressed the growth and migration of ccRCC cells. Levels of Mul1 protein and mRNA were significantly reduced so that autophagy flux was likely blocked in ccRCC tissues, which is potentially correlated with enhancement of malignancy of ccRCC and impairment of patient survival. Therefore, Mul1 may promote autophagy to suppress the development of ccRCC.

show abstract

“…Moreover, other studies reported MUL1 involvement in regulation of seleniteinduced mitophagy. 5 Selenite at low doses is known to induce mitophagy. 5 Again, ligase activity is crucial for this process.…”

mentioning

confidence: 99%

“…5 Selenite at low doses is known to induce mitophagy. 5 Again, ligase activity is crucial for this process. Selenium role as a chemoprotective agent should be investigated further, and other agents capable of MUL1 upregulation should be sought.…”

mentioning

confidence: 99%

MUL1-A new potential for a therapeutic target for Parkinson's disease a commentary on “MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin” by Yun and colleagues (eLife 2014; 3: 1-26)

Olszewska

Lynch

2016

Mov Disord.

View full text Add to dashboard Cite

Mitochondrial dysfunction, impaired protein degradation, oxidative damage, and impaired mitophagy all have important roles in the pathogenesis of Parkinson's disease (PD). Familial PD studies advanced our understanding of PD pathogenesis. For example, mutations in relevant genes PINK1 (PTEN-induced putative kinase) and parkin cause autosomal recessive young-onset PD; PINK1 activates Parkin (E3-ubiquitin ligase), which then phosphorylates ubiquitin, 1 leading to the elimination of damaged mitochondria (mitophagy). PINK1 and parkin mutations disrupt this pathway, 1 and parkin enhancement is a proposed therapeutic approach in PD. In mice, loss of PINK1 and parkin results only in subtle PD signs, 2 unlike in humans where levodoparesponsive parkinsonism develops. Intriguingly, 1 patient with parkin homozygous mutation and confirmed functional parkin loss surprisingly did not develop PD even by age 66. Furthermore, ubiquitination of fusion mediator-mitofusin (mfn2; 4 part of the mitochondrial network and mitophagy cascade), was impaired in this patient, and there was no observed compensation for the impaired mfn2 ubiquitination. 3 This suggests the existence of other compensatory proteins or pathways that may prove useful for PD therapeutics.Yun and colleagues identified a novel ligase that rescues the defects caused by mutations in PINK1 and parkin mutations in Drosophila called MUL1 (Mitochondrial E3-Ubiquitin Protein Ligase 1). MUL1 guards mitochondrial homeostasis and promotes fragmentation of mitochondria by stabilizing dynamin-related protein (drp1) or degrading mitofusin (mfn). It is not known if increased mfn/decreased drp1 alone causes mutant phenotypes. MUL1 seems to act in parallel with PINK1 and parkin. Loss of PINK1 or parkin combined with additional loss of MUL1 results in exaggerated mitochondrial damage and more severe PD phenotype in flies when compared with loss of PINK1 or parkin alone. When MUL1 is absent, any compensation for PINK1 or parkin defects is impossible. Moreover, decreased mfn ubiquitination with an exaggerated phenotype as a result of the loss of both MUL1 and parkin was confirmed in mouse cortical neurons. MUL1 upregulation rescues mitochondrial damage caused by PINK1 or parkin deficit, and ligase activity is crucial for this rescue. Yun and colleagues demonstrated that mitofusin overexpression, but not dynamin-related protein loss, results in mutant phenotypes in Drosophila and mice. MUL1 and parkin can rescue the PINK1 mutants independently.This paper highlights that new PD-targeted therapeutic possibilities involving MUL1 are promising. Moreover, other studies reported MUL1 involvement in regulation of seleniteinduced mitophagy.5 Selenite at low doses is known to induce mitophagy.5 Again, ligase activity is crucial for this process. Selenium role as a chemoprotective agent should be investigated further, and other agents capable of MUL1 upregulation should be sought.In conclusion, the MUL1 pathway may be an important covariable in PINK1 and parkin mutation carriers. Furthermore, MUL...

show abstract

Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy

Cited by 124 publications

References 55 publications

The Arabidopsis E3 Ubiquitin Ligase SP1 Targets to Chloroplasts, Peroxisomes, and Mitochondria

The Arabidopsis E3 Ubiquitin Ligase SP1 Targets to Chloroplasts, Peroxisomes, and Mitochondria

Mitochondrial E3 ubiquitin ligase 1 promotes autophagy flux to suppress the development of clear cell renal cell carcinomas

MUL1-A new potential for a therapeutic target for Parkinson's disease a commentary on “MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin” by Yun and colleagues (eLife 2014; 3: 1-26)

Contact Info

Product

Resources

About