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Insulin signaling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat) Mus Musculus (mouse)

SUBMITTER: Barbara Steigenberger

LAB HEAD: Prof. Angelika Harbauer

PROVIDER: PXD045621 | Pride | 2024-02-23

REPOSITORIES: Pride

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Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy

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

Parkinson Phenotype in Aged PINK1-Deficient Mice Is Accompanied by Progressive Mitochondrial Dysfunction in Absence of Neurodegeneration

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

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2014-11-04 | GSE60413 | GEO

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Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy

Project description:Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy

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Roles of PINK1 in regulation of systemic growth inhibition induced by mutations of PTEN in Drosophila

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2021-02-20 | GSE167076 | GEO

SWATH-MS Analysis of Striatal Synaptic Mitochondria from Pink1 KO rats

Project description:This study investigates the proteomic alterations in striatal synaptic mitochondria isolated from 3-month-old wild-type and Pink1 KO rats using the SWATH-MS strategy. This dataset consists of 32 raw MS files, comprising 8 DIA (SWATH) and 24 DDA runs on a TripleTOF 5600 (SCIEX). Our findings revealed synaptic mitochondrial proteomic changes due to loss of Pink1.

2016-09-28 | PXD004558 | Pride

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