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Bus, C.* ; Zizmare, L.* ; Feldkaemper, M.* ; Geisler, S.* ; Zarani, M.* ; Schaedler, A.* ; Klose, F.* ; Admard, J.* ; Mageean, C.J.* ; Arena, G.* ; Fallier-Becker, P.* ; Ugun-Klusek, A.* ; Maruszczak, K.K.* ; Kapolou, K.* ; Schmid, B.* ; Rapaport, D.* ; Ueffing, M.* ; Casadei, N.* ; Kruger, R.* ; Gasser, T.* ; Weisenhorn, D.M. ; Kahle, P.J.* ; Trautwein, C.* ; Gloeckner, C.J.* ; Fitzgerald, J.C.*

Human dopaminergic neurons lacking PINK1 exhibit disrupted dopamine metabolism related to vitamin B6 co-factors.

iScience 23:101797 (2020)

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	Open Access Gold

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PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated.Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme mAconitase, accumulation of NAD(+), and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches.We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Molecular Biology ; Molecular Neuroscience ; Omics ; Stem Cells Research; Loss-of-function; Parkinsons-disease; Complex I; Mitochondrial-membrane; Mitophagy; Mutations; Ubiquitin; Promotes; Neurodegeneration; Drosophila-pink1

ISSN (print) / ISBN 2589-0042

e-ISSN 2589-0042

Journal iScience

Quellenangaben Volume: 23, Issue: 12, Article Number: 101797

Publisher Elsevier

Publishing Place Amsterdam ; Bosten ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Developmental Genetics (IDG)

Grants Fonds National de Recherche de Luxembourg (FNR) within MiRisk project
German Research Council (DFG), Research Training Group (RTG)
German Center for Neurodegenerative Diseases (DZNE)
Michael J Fox Foundation for Parkinson's Research
Nottingham Trent University Independent Research Fellowship Scheme (UK)
Fonds National de Recherche de Luxembourg (FNR) within the National Center for Excellence in Research on Parkinson's disease (NCER-PD)
DFG-RTG MOMbrane
German Science Foundation within the Collaborative Research Centre
Initiative and Network Fund of the Helmholtz Association
Germany Ministry of Education and Research (BMBF) e:Med Demonstrator project MitoPD