Roles of PINK1 in regulation of systemic growth inhibition induced by mutations of PTEN in Drosophila
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PROVIDER: PRJNA702921 | ENA |
REPOSITORIES: ENA
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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:PTEN-induced kinase 1 (PINK1) is a very short-lived protein that is required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated with and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane protein Synaptojanin 2 Binding Protein (SYNJ2BP) and Synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for activation of mitophagy.
2022-01-14 | GSE193443 | GEO
Project description:Loss of function in the PTEN-induced kinase 1 gene (Pink1) causes an early-onset, autosomal recessive form of PD. The translational Pink1-/- rat shows cranial sensorimotor deficits including: declines in ultrasonic vocalization, negative impacts on social vocal function, and alterations to thyroarytenoid muscle structure. The aim of this study was to identify differentially expressed genes using RNA-sequencing and bioinformatic analysis of the thyroarytenoid muscle of male Pink1-/- rats compared to wildtype controls. To construct gene co-expression networks and gene modules, a WGCNA was used to identify biological networks of interest including where Pink1 was a central node with interconnecting genes. Data are congruent with previous findings demonstrating changes to thyroarytenoid muscle structure. These data are consistent with the hypothesis that differences in peripheral biology may influence the early pathogenesis of vocalizations at the level of the thyroarytenoid muscle.
2020-05-27 | GSE151209 | GEO
Project description:Th17-related genes increased in T cells from PINK1-deficient mice. Th17 and Treg cells were increased and decreased in PINK1-deficient cells, respectively, and phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased in PINK1-deficient cells.
2024-01-29 | GSE254099 | 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:Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of M-NM-1-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Thus, aging Pink1M-bM-^HM-^R/M-bM-^HM-^R mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death. Transcriptome microarray data of Pink1-/- mouse brains in absence of a stressor, even at old age, show remarkably sparse dysregulations. See Gispert-S et al 2009 PLOS ONE. Factorial design comparing Pink1 knock-out mice with wild type littermates in three different tissues (striatum, midbrain, cerebellum at four different timepoints (6, 12, 14 weeks, and 18 month)
2014-11-04 | E-GEOD-60413 | biostudies-arrayexpress
Project description:Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of α-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Thus, aging Pink1−/− mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death. Transcriptome microarray data of Pink1-/- mouse brains in absence of a stressor, even at old age, show remarkably sparse dysregulations. See Gispert-S et al 2009 PLOS ONE.
2014-11-04 | GSE60413 | GEO
Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.
2020-10-15 | PXD016184 | Pride
Project description:Global analysis of transcriptional changes in Drosophila pink1 mutants.
2013-12-02 | E-MEXP-3645 | biostudies-arrayexpress
Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.
2012-12-01 | E-GEOD-35670 | biostudies-arrayexpress