iScience (Dec 2020)
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 Gasser,
- Daniela M. Vogt Weisenhorn,
- Philipp J. Kahle,
- Christoph Trautwein,
- Christian J. Gloeckner,
- Julia C. Fitzgerald
Affiliations
- Christine Bus
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany; DZNE – German Center for Neurodegenerative Diseases, Tübingen, Germany
- Laimdota Zizmare
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
- Marita Feldkaemper
- Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
- Sven Geisler
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany
- Maria Zarani
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany
- Anna Schaedler
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany
- Franziska Klose
- Core Facility for Medical Bioanalytics, University of Tübingen, Center for Ophthalmology, Institute for Ophthalmic Research, Tübingen, Germany
- Jakob Admard
- NGS Competence Center Tübingen, Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany
- Craig J. Mageean
- DZNE – German Center for Neurodegenerative Diseases, Tübingen, Germany; Core Facility for Medical Bioanalytics, University of Tübingen, Center for Ophthalmology, Institute for Ophthalmic Research, Tübingen, Germany
- Giuseppe Arena
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg
- Petra Fallier-Becker
- Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany
- Aslihan Ugun-Klusek
- School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Klaudia K. Maruszczak
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
- Konstantina Kapolou
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany
- Benjamin Schmid
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany
- Doron Rapaport
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
- Marius Ueffing
- Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany; Core Facility for Medical Bioanalytics, University of Tübingen, Center for Ophthalmology, Institute for Ophthalmic Research, Tübingen, Germany
- Nicolas Casadei
- NGS Competence Center Tübingen, Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany
- Rejko Krüger
- Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg
- Thomas Gasser
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany; DZNE – German Center for Neurodegenerative Diseases, Tübingen, Germany
- Daniela M. Vogt Weisenhorn
- Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Munich-Neuherberg, Germany
- Philipp J. Kahle
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany; DZNE – German Center for Neurodegenerative Diseases, Tübingen, Germany
- Christoph Trautwein
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
- Christian J. Gloeckner
- DZNE – German Center for Neurodegenerative Diseases, Tübingen, Germany; Core Facility for Medical Bioanalytics, University of Tübingen, Center for Ophthalmology, Institute for Ophthalmic Research, Tübingen, Germany
- Julia C. Fitzgerald
- Department of Neurodegenerative Diseases, Centre of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried Müller Strasse 27, 72076, Tübingen, Germany; Corresponding author
- Journal volume & issue
-
Vol. 23,
no. 12
p. 101797
Abstract
Summary: 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.