title: Inhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1-/-zebrafish.
abstract: Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of early onset Parkinson's disease (PD). Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter (MCU), located in the inner mitochondrial membrane, prevents dopaminergic neuronal cell loss in pink1Y431* mutant zebrafish (Danio rerio) via rescue of mitochondrial respiratory chain function. In contrast, genetic inactivation of the voltage dependent anion channel 1 (VDAC1), located in the outer mitochondrial membrane, did not rescue dopaminergic neurons in PINK1 deficient D. rerio. Subsequent gene expression studies revealed specific upregulation of the mcu regulator micu1 in pink1Y431* mutant zebrafish larvae and inactivation of micu1 also results in rescue of dopaminergic neurons. The functional consequences of PINK1 deficiency and modified MCU activity were confirmed using a dynamic in silico model of Ca2+triggered mitochondrial activity. Our data suggest modulation of MCU-mediated mitochondrial calcium homeostasis as a possible neuroprotective strategy in PINK1 mutant PD.
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland.|Bateson Centre, University of Sheffield, Sheffield, UK.|Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Smijin
authors.initials: S
authors.lastname: Soman
authors.affiliation: Bateson Centre, University of Sheffield, Sheffield, UK.|Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Keatinge
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Moein
authors.affiliation: Bateson Centre, University of Sheffield, Sheffield, UK.|Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Da Costa
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Mortiboys
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg.|National Centre for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Skupin
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland.|Bateson Centre, University of Sheffield, Sheffield, UK.|Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Sugunan
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Bazala
authors.affiliation: International Institute of Molecular and Cell Biology, Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Kuznicki
authors.affiliation: Bateson Centre, University of Sheffield, Sheffield, UK.|Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bandmann
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015854:Up-Regulation; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002118:Calcium; D015220:Calcium Channels; D017346:Protein Serine-Threonine Kinases; D050995:Voltage-Dependent Anion Channel 1; C034703:mitochondrial calcium uniporter; C558157:Pink1 protein, zebrafish; D029961:Zebrafish Proteins; D000099202:PTEN-Induced Putative Kinase
keywords: Danio rerio; MICU1; Parkinson's disease; Ruthenium red