title: Catecholamine metabolism drives generation of mitochondrial DNA deletions in dopaminergic neurons.
abstract: Accumulation of mitochondrial DNA deletions is observed especially in dopaminergic neurons of the substantia nigra during ageing and even more in Parkinson's disease. The resulting mitochondrial dysfunction is suspected to play an important role in neurodegeneration. However, the molecular mechanisms involved in the preferential generation of mitochondrial DNA deletions in dopaminergic neurons are still unknown. To study this phenomenon, we developed novel polymerase chain reaction strategies to detect distinct mitochondrial DNA deletions and monitor their accumulation patterns. Applying these approaches in in vitro and in vivo models, we show that catecholamine metabolism drives the generation and accumulation of these mitochondrial DNA mutations. As in humans, age-related accumulation of mitochondrial DNA deletions is most prominent in dopaminergic areas of mouse brain and even higher in the catecholaminergic adrenal medulla. Dopamine treatment of terminally differentiated neuroblastoma cells, as well as stimulation of dopamine turnover in mice over-expressing monoamine oxidase B both induce multiple mitochondrial DNA deletions. Our results thus identify catecholamine metabolism as the driving force behind mitochondrial DNA deletions, probably being an important factor in the ageing-associated degeneration of dopaminergic neurons.
authors.affiliation: 1 Centre for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Köln, Germany.
authors.forename: Johannes F G
authors.initials: JF
authors.lastname: Neuhaus
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Baris
authors.forename: Simon
authors.initials: S
authors.lastname: Hess
authors.forename: Natasha
authors.initials: N
authors.lastname: Moser
authors.forename: Hannsjörg
authors.initials: H
authors.lastname: Schröder
authors.forename: Shankar J
authors.initials: SJ
authors.lastname: Chinta
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
authors.forename: Peter
authors.initials: P
authors.lastname: Kloppenburg
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002395:Catecholamines; D004272:DNA, Mitochondrial
keywords: Parkinson’s disease, mtDNA deletion; dopamine; mitochondrial dysfunction