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

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. ORCID: 0000-0002-0199-0275, Maruszczak, K.K., Kapolou, K., Schmid, B., Rapaport, D., Ueffing, M., Casadei, N., Krüger, R., Gasser, T., Vogt Weisenhorn, D.M., Kahle, P.J., Trautwein, C., Gloeckner, C.J. and Fitzgerald, J.C., 2020. Human dopaminergic neurons lacking PINK1 exhibit disrupted dopamine metabolism related to vitamin B6 co-factors. iScience, 23 (12): 101797. ISSN 2589-0042

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Abstract

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.

Item Type: Journal article
Publication Title: iScience
Creators: 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., Krüger, R., Gasser, T., Vogt Weisenhorn, D.M., Kahle, P.J., Trautwein, C., Gloeckner, C.J. and Fitzgerald, J.C.
Publisher: Elsevier
Date: 18 December 2020
Volume: 23
Number: 12
ISSN: 2589-0042
Identifiers:
NumberType
10.1016/j.isci.2020.101797DOI
S2589-0042(20)30994-9Publisher Item Identifier
1391307Other
Rights: © 2020 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Divisions: Schools > School of Science and Technology
Record created by: Linda Sullivan
Date Added: 27 Nov 2020 13:14
Last Modified: 04 Jan 2021 10:33
URI: http://irep.ntu.ac.uk/id/eprint/41705

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