Dopaminergic neurons preferentially accumulate mtDNA rearrangements
Abstract
High levels of mitochondrial DNA (mtDNA) deletions have been described in the substantia nigra. However, the mechanisms involved are poorly understood. We found that transient expression of a mitochondrial targeted restriction endonuclease (mitoPstI) in mice leads to an accumulation of mtDNA rearrangements that involve both the PstI cleavage sites and unrelated specific regions of the mtDNA, including the MTERF1 binding site and the edge of the D-loop. This pattern of rearrangements after double-strand breaks supports the presence of recombination hotspots in the mtDNA. Transient expression of mitoPstI in dopaminergic neurons led to further accumulation of mtDNA rearrangements in dopaminergic neurons after expression was suppressed, a pattern that was not observed in glutamatergic neurons. This accumulation was also blunted when a mtDNA replisome factor was absent, suggesting that robust mtDNA replication is required for the accumulation of preexisting mtDNA rearrangements in dopaminergic neurons over time.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (9)
Tania Arguello
Department of Neurology and Cell and Systems Biology, University of Miami Miller School of Medicine
Christian D. Alcalde Pretel
MD/PhD Program and Department of Cell and Systems Biology, University of Miami Miller School of Medicine
Nadee Nissanka
Department of Neurology and Cell and Systems Biology, University of Miami Miller School of Medicine
Derek Van Booven
John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
Milena Pinto
Department of Neurology and Cell and Systems Biology, University of Miami Miller School of Medicine
Monica Rodriguez-Silva
Department of Neurology and Cell and Systems Biology, University of Miami Miller School of Medicine
Lise-Michelle Theard
Department of Neurology and Cell and Systems Biology, University of Miami Miller School of Medicine
Anthony J. Griswold
John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
Carlos T. Moraes
Department of Neurology and Cell and Systems Biology, University of Miami Miller School of Medicine