Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors

Christine Bus, Laimdota Zizmare, Marita Feldkaemper, Sven Geisler, Maria Zarani, Anna Schaedler, Franziska Klose, Jakob Admard, Craig J. Mageean, Giuseppe Arena, Petra Fallier-Becker, Aslihan Ugun-Klusek, Klaudia K. Maruszczak, Konstantina Kapolou, Benjamin Schmid, Doron Rapaport, Marius Ueffing, Nicolas Casadei, Rejko Krüger, Thomas GasserDaniela M. Vogt Weisenhorn, Philipp J. Kahle, Christoph Trautwein, Christian J. Gloeckner, Julia C. Fitzgerald*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Article number101797
JournaliScience
Volume23
Issue number12
DOIs
Publication statusPublished - 18 Dec 2020

Keywords

  • Molecular Biology
  • Molecular Neuroscience
  • Omics
  • Stem Cells Research

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