Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE193443 | GEO | 2022/01/14
REPOSITORIES: GEO
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Project description:Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.
2019-06-22 | GSE126910 | GEO
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
Project description:Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early onset Parkinson disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane (OMM) forming a high molecular weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates ubiquitin, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved, remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress, such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 NT-CTE module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.
2024-03-02 | PXD047765 | Pride
Project description:Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy
| PRJNA796269 | ENA
Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
2023-09-24 | GSE243532 | GEO
Project description:The maintenance of mitochondrial homeostasis requires PTEN-induced kinase 1 (PINK1)-dependent mitophagy, and mutations in PINK1 are associated with Parkinson's disease (PD). PINK1 is also downregulated in tumor cells with PTEN mutations. However, there is limited information concerning the role of PINK1 in tissue growth and tumorigenesis. Here, we show that loss of pink1 caused multiple growth defects independent of its pathological target, Parkin. Moreover, knocking-down pink1 in muscle cells induced hyperglycemia and limited systemic organismal growth by induction of Imaginal morphogenesis protein-Late 2 (ImpL2). Similarly, disrupting PTEN activity in multiple tissues impaired systemic growth by reducing pink1 expression, resembling wasting-like syndrome in cancer patients. Furthermore, re-expression of PINK1 fully rescued defects in carbohydrate metabolism and systemic growth induced by the tissue-specific pten mutations. Our data suggest a new function for PINK1 in regulating systemic growth in Drosophila, and shed light on its role in wasting in context of PTEN mutations.
2021-02-20 | GSE167076 | GEO
Project description:Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 mRNA by tethering it to the mitochondrial surface. Here, we report that inhibition of AMPK by activation of the insulin signaling cascade prevents Pink1 mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Interestingly, loss of mitochondrial Pink1 mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin-resistance in vitro by the key genetic Alzheimer-risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signaling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.
2024-02-23 | PXD045621 | Pride
Project description:Dysregulated inflammation is a key driver of disease following infection with the globally important human pathogens, Zika virus (ZIKV) and dengue virus. However, specific mechanisms of inflammation are not well defined. Here, we demonstrate that ZIKV antagonizes mitophagy, or the process of selective degradation of damaged mitochondria. The mechanism of antagonism was through interactions between NS5 and the host protein Ajuba to prevent Ajuba translocation to depolarized mitochondria. We further identify a role of Ajuba in mitophagy through augmenting PINK1 kinase activity. Mitophagy suppression in infected Ajuba-/- cells amplified the cellular integrated stress response (ISR) to promote ZIKV replication, and increased pro-inflammatory cytokine expression dependent on the ISR kinase, PKR. Thus, ZIKV suppresses mitophagy to favor replication and this failure of mitochondrial quality control is translated to inflammation by PKR, suggesting new therapeutic targets to treat flavivirus disease.
2021-09-08 | GSE162688 | GEO
Project description:Enhancing mitophagy, a naturally-occurring cellular process for elimination of damaged mitochondria, holds great promise for the intervention of many human diseases. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce ubiquitination and subsequent proteasome-mediated degradation of a target protein through simultaneously binding to the target protein and an E3 ubiquitin ligase. However, the narrow cavity of the proteasome prevents the degradation of mitochondria. Here we show that the E3 ubiquitin ligase MAP3K1, when recruited to the outer mitochondria membrane (OMM) protein TSPO by our PROTAC-designed molecules (termed “mitophagy-enhancing chimeras”, or MECs), induced extensive K63 ubiquitination of TSPO and other OMM proteins, reminiscent of the PINK1-activated Parkin, without triggering proteasome-mediated degradation of TSPO. Aided by NBR1 and Nur77, this increased K63 ubiquitination of OMM proteins triggered mitophagy exclusively for damaged mitochondria, leading to improved mitochondria function and diminished cellular ROS. With the capability to enhance mitophagy at low nanomolar concentrations, MECs effectively inhibited NLRP3 inflammasome activation, abrogated acetaminophen-induced acute liver injury and mitigated high-fat diet-induced obesity in mice. Our work provided a proof-of-concept for developing unconventionally-acting PROTACs to achieve degradation of damaged mitochondria and possibly other organelles.
2024-02-08 | GSE255354 | GEO
Project description:Defects in the clearance of dysfunctional mitochondria contribute to the development of heart failure and several neurological disorders including Parkinson’s disease (PD). The mitophagic signaling pathways that control the rapid recognition, ubiquitin-tagging and encasement of dysfunctional mitochondria into protective autophagosomes have been well characterized and a major mechanism involves coordinated control of the serine/threonine kinase PINK1 and the E3 ubiquitin ligase, Parkin. What is less known is how such clearance processes are spatially controlled. Indeed, while recent studies indicate that actin remodeling can facilitate Parkin-dependent mitochondrial clearance, the underlying players that coordinate localized cytoskeletal remodeling to facilitate the trafficking and clearance of damaged mitochondria remain largely unclear. Herein, we demonstrate that the RhoGAP, GRAF1 (Arhgap26), is a PINK1 substrate that controls mitophagy. Cardiomyocyte-restricted GRAF1 depletion led to accumulation of dysfunctional mitochondria and attenuated stress-induced metabolic adaptation in adult hearts. GRAF1 was required for mitochondria release from F-actin anchors, facilitated mitochondria capture by autophagosomes by enhancing Parkin-LC3 interactions, and promoted mitochondria-associated Arp2/3-dependent actin remodeling. This study employs mass spectrometry-based proteomics to elucidate the interactome of GRAF1, focusing on the protein-protein interactions facilitated by GRAF1 phosphorylation.
2024-01-26 | PXD043212 | Pride