Universität zu Köln

Ricke, Konrad M., Pass, Thomas, Kimoloi, Sammy, Faehrmann, Kai, Juengst, Christian, Schauss, Astrid, Baris, Olivier R., Aradjanski, Marijana, Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517, Faelker, Therese M. Eriksson, Bergami, Matteo and Wiesner, Rudolf J. (2020). Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons. J. Neurosci., 40 (9). S. 1975 - 1987. WASHINGTON: SOC NEUROSCIENCE. ISSN 1529-2401

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Abstract

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ricke, Konrad M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pass, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kimoloi, Sammy UNSPECIFIED UNSPECIFIED UNSPECIFIED Faehrmann, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED Juengst, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Baris, Olivier R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aradjanski, Marijana UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED orcid.org/0000-0002-5472-3517 UNSPECIFIED Faelker, Therese M. Eriksson UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergami, Matteo UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesner, Rudolf J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-343951
DOI:	10.1523/JNEUROSCI.1345-19.2019
Journal or Publication Title:	J. Neurosci.
Volume:	40
Number:	9
Page Range:	S. 1975 - 1987
Date:	2020
Publisher:	SOC NEUROSCIENCE
Place of Publication:	WASHINGTON
ISSN:	1529-2401
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LINKED ISOCITRATE DEHYDROGENASE; K-ATP CHANNELS; SUBSTANTIA-NIGRA; PARKINSONS-DISEASE; DNA DELETIONS; 2-OXOGLUTARATE DEHYDROGENASE; OXIDANT STRESS; CYTOCHROME-C; CA-2+ IONS; RAT-HEART Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34395