TY - JOUR
T1 - Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors
AU - Bus, Christine
AU - Zizmare, Laimdota
AU - Feldkaemper, Marita
AU - Geisler, Sven
AU - Zarani, Maria
AU - Schaedler, Anna
AU - Klose, Franziska
AU - Admard, Jakob
AU - Mageean, Craig J.
AU - Arena, Giuseppe
AU - Fallier-Becker, Petra
AU - Ugun-Klusek, Aslihan
AU - Maruszczak, Klaudia K.
AU - Kapolou, Konstantina
AU - Schmid, Benjamin
AU - Rapaport, Doron
AU - Ueffing, Marius
AU - Casadei, Nicolas
AU - Krüger, Rejko
AU - Gasser, Thomas
AU - Vogt Weisenhorn, Daniela M.
AU - Kahle, Philipp J.
AU - Trautwein, Christoph
AU - Gloeckner, Christian J.
AU - Fitzgerald, Julia C.
N1 - Funding Information:
AU-K is supported by Nottingham Trent University Independent Research Fellowship Scheme (UK). This work was supported by research grants from Fonds National de Recherche de Luxembourg ( FNR ) within the National Center for Excellence in Research on Parkinson's disease (NCER-PD) and MiRisk project [ C17/BM/11676395 ] for RK and GA. DM and KM also acknowledge DFG -RTG MOMbrane ( GRK 2364 ). DVW acknowledges support from the German Science Foundation within the Collaborative Research Centre (CRC) 870, and the Initiative and Network Fund of the Helmholtz Association within the ‘ExNet-0041-Phase2-3 (“SyNergy-HMGU”)’ project.
Funding Information:
We greatly acknowledge funding from the Germany Ministry of Education and Research (BMBF) e:Med Demonstrator project MitoPD ( FKZ 031A430A ). JCF greatly acknowledges support from The German Research Council ( DFG ), Research Training Group ( RTG ) MOMbrane– GRK 2364 , And also, The German Center for Neurodegenerative Diseases ( DZNE ) and The Michael J Fox Foundation for Parkinson's Research ( MJFF - 15744 ).
Funding Information:
We greatly acknowledge funding from the Germany Ministry of Education and Research (BMBF) e:Med Demonstrator project MitoPD (FKZ 031A430A). JCF greatly acknowledges support from The German Research Council (DFG), Research Training Group (RTG) MOMbrane?GRK 2364, And also, The German Center for Neurodegenerative Diseases (DZNE) and The Michael J Fox Foundation for Parkinson's Research (MJFF-15744). AU-K is supported by Nottingham Trent University Independent Research Fellowship Scheme (UK). This work was supported by research grants from Fonds National de Recherche de Luxembourg (FNR) within the National Center for Excellence in Research on Parkinson's disease (NCER-PD) and MiRisk project [C17/BM/11676395] for RK and GA. DM and KM also acknowledge DFG-RTG MOMbrane (GRK 2364). DVW acknowledges support from the German Science Foundation within the Collaborative Research Centre (CRC) 870, and the Initiative and Network Fund of the Helmholtz Association within the ?ExNet-0041-Phase2-3 (?SyNergy-HMGU?)? project. We would like to thank the iPS cell facility at the HMGU Munich and Annerose Kurz-Drexler as well as Dr. Florian Giesert for generating the hiPSCs and the respective gene-corrected line derived from patients carrying the PINK1 Q126P mutation. We also thank Christine Klein and Philipp Seibler (University of L?beck, Germany) who kindly shared the human iPSC lines from PD patients carrying the PINK1 Q456X mutation and Jens Schwamborn and Javier Jarazo (LCSB, University of Luxembourg, Luxembourg) for kindly providing their corresponding gene-corrected controls to prepare RNA. We would like to acknowledge The Werner Siemens Imaging Center (WSIC) and Bernd Pichler for access to the NMR spectroscopy for the metabolomics experiments. We thank students and interns in the Fitzgerald lab (Malina John, Max Mattheuer and Lisa Schwarz) who contributed toward establishing and optimizing methodologies. Also E. Ellen Billett for critical review. Conceptualization, JCF; Methodology, JCF, CB, BS, CJG, CT, DV-W, DR; Validation, JCF, CB, MZ, AS, GA.; Formal Analysis, JCF, MF, AS, CB, KK, CJG, PF-B, AU-K, JA, LZ, CT; Investigation, JCF, CB, MF, SG, MZ, LS, CB, KK, NC, PF-B, AS, FK, CM, JA, AU-K, LZ, KM, GA, CT; Writing?Original Draft, JCF; Writing?Review & Editing, JCF, SG, PK, AU-K, LZ, CB; Visualization, JCF, PK, SG, CJG, CB, JA, LZ, NC; Funding Acquisition, JCF, CJG, MU, RK, TG. and PK; Resources, TG, MU, NC, CT; Supervision, JCF, TG. The authors declare no conflict of interest.
Publisher Copyright:
© 2020 The Authors
PY - 2020/12/18
Y1 - 2020/12/18
N2 - 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.
AB - 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.
KW - Molecular Biology
KW - Molecular Neuroscience
KW - Omics
KW - Stem Cells Research
UR - http://www.scopus.com/inward/record.url?scp=85106812130&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101797
DO - 10.1016/j.isci.2020.101797
M3 - Article
AN - SCOPUS:85106812130
SN - 2589-0042
VL - 23
JO - iScience
JF - iScience
IS - 12
M1 - 101797
ER -