Loss of the nucleolar DUB USP36 impairs Parkin dependent mitophagy via downregulation of autophagic components
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ABSTRACT:
PROVIDER: PRJNA516404 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8471380.fastq.gz | Fastqsanger.gz | |||
| SRR8471381.fastq.gz | Fastqsanger.gz | |||
| SRR8471382.fastq.gz | Fastqsanger.gz | |||
| SRR8471383.fastq.gz | Fastqsanger.gz | |||
| SRR8471374.fastq.gz | Fastqsanger.gz |
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Project description:The Parkin dependent final elimination of defective mitochondria is halted by loss of the nucleolar DUB USP36. The authors suggest a general failure in autophagy induction due to a decline in Beclin-1 and ATG14 levels. Reduction of the epigenetic mark histone 2B lysine 120 ubiquitination possibly contributes to the observed phenotype.
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Project description:Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis to cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA (mtDNA) content and mitochondrial function are significantly increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion robustly elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated Nqo1. Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mtDNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.
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Project description:PINK1/parkin-dependent mitophagy initially involves (phospho) ubiquitin-proteasome-dependent degradation of certain outer mitochondrial membrane (OMM) proteins (e.g. mitofusins) and then the recruitment of autophagy effectors to more stable ubiquitinated OMM proteins. It is widely assumed that such ubiquitinated mitochondria are ultimately degraded via wholesale mitophagy. However, we demonstrate that mitochondrial degradation occurs via step-wise delivery of separate mitochondrial sub-compartments to lysosomes. OMM and inner mitochondrial material appears to become separately isolated for autophagolysosomal degradation, not only in parkin-overexpressing HeLa cells but also in cells that express endogenous parkin (human embryonic kidney cells and neural progenitor cells) with slower mitophagy kinetics. The remaining inner mitochondrial material becomes degraded only after much prolonged membrane depolarization, involving another proteasome-sensitive step. These combined microscopy and proteomics analyses lend support to the idea that cell stress-induced parkin-dependent mitophagy is a complex regulated multi-step process with distinct sub-compartments separately targeted to autophagic degradation.
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Project description:The random-pattern skin flap is a crucial technique in reconstructive surgery and flap necrosis caused by ischemia/reperfusion injury is a major postoperative complication. Herein, we investigated the mechanism of mitophagy induced by Melatonin (ML) and its effect on the survival of skin flaps. Our results demonstrated that ML could activate mitophagy, ameliorate oxidative stress and alleviate apoptosis in TBHP-stimulated human umbilical vein endothelial cells in vitro. Inhibiting ML-induced mitophagy considerably abolished its protective effects. Moreover, knockdown of Parkin by siRNA inhibited ML-induced mitophagy, and subsequently exacerbated oxidative stress and apoptosis. Further study demonstrated that inhibition of AMPK reversed these protective effects of ML and downregulated the expression of TFEB. In the vivo study, ML effectively promoted flap survival by activating mitophagy and subsequently ameliorating oxidative stress and mitigating apoptosis. These results established that ML is a potent agent capable for increasing random-pattern skin flap survival by activating Parkin-dependent mitophagy through the AMPK-TFEB signaling pathway.
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Project description:Elevated or chronic innate immune activation plays a role in the progression of metabolic diseases such as diabetes, yet the influence of innate immune signaling on pancreatic β-cells is not well characterized. Here we report that TRAF6, an E3 ubiquitin ligase downstream of TLR signaling, maintains β-cell function during diet-induced obesity. Deletion or inhibition of TRAF6 impairs glucose homeostasis, mitochondrial function, and mitophagy during metabolic stress in both mouse and human islets. The combination of TRAF6 deficiency and palmitate exposure reduces localization of mitophagy machinery, such as BNIP3, to the mitochondria. Interestingly, co-deletion of Parkin restores glucose-stimulated insulin section, mitochondrial bioenergetics, and mitophagy. These findings suggest that Parkin-independent mitophagy mechanisms may be important for maintenance of β-cell function during metabolic stress.
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2022-01-17 | PXD027586 | Pride
Project description:The PINK1/Parkin pathway is responsible for targeting damaged mitochondria for degradation via mitophagy. Because genetic evidence links impaired mitophagy to Parkinson’s disease, pharmacologic enhancement of mitophagy represents a promising disease-modifying strategy. Here, we characterize two pharmacological mitophagy activators: a new Parkin activator, FB231, described here and the reported PINK1 activator MTK458. We demonstrate that both compounds activate their targets and lower the threshold for PINK1/Parkin-mediated mitophagy induced by mitochondrial stressors. Using global proteomics, however, we also find that FB231 and MTK458 exert mild mitochondrial stress that leads to cleavage of OPA1 and activation of the integrated stress response, in a PINK1/Parkin-independent manner. Both compounds cause mitochondrial stress and thereby sensitizes cells to mitophagy induction by classical mitochondria toxins. We provide a model that rationalizes this hitherto unknown mechanism for mitophagy activators, whereby normally “silent” mitochondrial toxins can act as potent PINK1/Parkin potentiators in the context of mitochondrial stress.
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Project description:Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood.We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes. 5 wild-type mouse hearts; 4 germline Parkin knockout mouse hearts Please note that the mouse cardiac examples were an adjunct to the Drosophila studies that comprised most of the associated publication. However, mRNA-sequencing was only performed on the mouse samples, not the Drosophila heart tubes.
2015-10-31 | E-GEOD-74517 | biostudies-arrayexpress
Project description:The protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed-forward mechanism involving ubiquitin (Ub) phosphorylation (pUb), Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins to support recruitment of mitophagy receptors. The ubiquitin ligase substrate receptor FBXO7/PARK15 is mutated in an early-onset parkinsonian-pyramidal syndrome. Previous studies have proposed a role for FBXO7 in promoting Parkin-dependent mitophagy. Here, we systematically examine the involvement of FBXO7 in depolarization and mtUPR-dependent mitophagy in the well-established HeLa and induced-neurons cell systems. We find that FBXO7-/- cells have no demonstrable defect in: 1) kinetics of pUb accumulation, 2) pUb puncta on mitochondria by super-resolution imaging, 3) recruitment of Parkin and autophagy machinery to damaged mitochondria, 4) mitophagic flux, and 5) mitochondrial clearance as quantified by global proteomics. Moreover, global proteomics of neurogenesis in the absence of FBXO7 reveals no obvious alterations in mitochondria or other organelles. These results argue against a general role for FBXO7 in Parkin-dependent mitophagy and point to the need for additional studies to define how FBXO7 mutations promote parkinsonian-pyramidal syndrome.
2023-06-19 | PXD037797 | Pride