Mitochondrial DNA and Neuroinflammation
Oxidative stress, mitochondrial dysfunction and DNA damage are hallmarks of neurodegenerative diseases. Genetics and especially environmental factors may affect disease etiology and progression. Toxicants found within the natural environment; air pollution, ozone, and cigarette smoke, increase the production of reactive oxygen species (ROS). In addition, pesticides like rotenone or the herbicide paraquat, alter normal electron flow within the respiratory chain to stimulate ROS-induced mtDNA damage. Both of these once commonly used agents have been associated with Parkinson’s disease.
Neurodegenerative diseases are pathological conditions that demonstrate progressive loss of neurons and synapses in regions of the central nervous system. These changes promote incremental deficits of cognitive and motor function as the individual ages. Activation of microglia, immune cells found in the brain, increases ROS production, causing additional decrements of mitochondrial function. This establishes a vicious cycle of further inflammation and ROS related damage.
Unmanaged ROS production leads to oxidation of mtDNA, its fragmentation and appearance in
the cytosol or extracellular spaces. The mitochondrial evolutionary bridge from bacteria causes these mtDNA fragments to be recognized as xenobiotics by the innate immune system. triggering the production pro-inflammatory molecules. Thus, mtDNA acting as an immune sentinel, triggers an inappropriate immune response. Maintenance of mtDNA integrity by the DNA repair pathways serves to keep mtDNA intact thereby preventing the initiation and perhaps over compensation of immune-inflammatory reactions in neurological diseases.