Article (Scientific journals)
Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors.
Bus, Christine; Zizmare, Laimdota; Feldkaemper, Marita et al.
2020In iScience, 23 (12), p. 101797
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Keywords :
Molecular Biology; Molecular Neuroscience; Omics; Stem Cells Research
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bus, Christine;  University of Tübingen > Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research,
Zizmare, Laimdota
Feldkaemper, Marita
Geisler, Sven;  Univeristy of Tübingen > Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research
Zarani, Maria;  Univerity of Tübingen > Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research
Schaedler, Anna;  Univerity of Tübingen > Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research
Klose, Franziska
Admard, Jakob
Mageean, Craig J.
ARENA, Giuseppe  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Fallier-Becker, Petra
Ugun-Klusek, Aslihan
Maruszczak, Klaudia K.
Kapolou, Konstantina;  Univerity of Tübingen
Schmid, Benjamin
Rapaport, Doron
Ueffing, Marius
Casadei, Nicolas
KRÜGER, Rejko ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Gasser, Thomas;  University of Tübingen > Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research
Vogt Weisenhorn, Daniela M.
Kahle, Philipp J.;  Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research > University of Tübingen
Trautwein, Christoph
Gloeckner, Christian J.
Fitzgerald, Julia C.;  University of Tübingen > Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research
More authors (15 more) Less
External co-authors :
yes
Language :
English
Title :
Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors.
Publication date :
2020
Journal title :
iScience
ISSN :
2589-0042
Publisher :
Elsevier, Cambridge, United States - Massachusetts
Volume :
23
Issue :
12
Pages :
101797
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR11676395 - Mitochondrial Risk Factors In Parkinson's Disease, 2017 (01/03/2018-31/08/2021) - Rejko Krüger
Commentary :
© 2020 The Authors.
Available on ORBilu :
since 30 December 2020

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