Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA

Author:

Buneeva Olga,Fedchenko Valerii,Kopylov ArthurORCID,Medvedev Alexei

Abstract

Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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