Mitochondrial DNA and Neuroinflammation

 

Oxidative stress, mitochondrial dysfunction and DNA damage are hallmarks of many chronic diseases. Genetics and especially environmental factors may affect disease etiology and progression. Toxicants found within the natural environment; air pollution, ozone, and cigarette smoke, exacerbate cellular sources of 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 the neurodegenerative disorder, 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.  Alterations in protein dynamics (misfolding, proteostasis, etc) and neuro-immune and -inflammation are mechanistic contributors to disease progression. Mitochondrial dysfunction can promote neuroinflammation while ROS production by immune cells, like brain microglia, cause additional decrements of mitochondrial function, creating a vicious cycle of ROS related damage. Compounding this cycle are other contributing factors. For example, cells deficient in mtDNA, containing mutant DNA, or with pharmacological-induced loss of energy production capacity, demonstrate compromised immune responsiveness. The intimate relationship between mitochondrial dysfunction and immunity is highlighted by individuals with primary mitochondrial diseases who may have existing cognitive and motor disabilities, and can also suffer from more frequent and/or prolonged infections that can be life threatening and precipitate neurological decompensation. Thus, there is an interdependent relationship between mitochondria, immunity and neurological function.

 

Numerous studies link mtDNA damage to the immune response.  Unmanaged oxidant production leading to oxidation of mtDNA, its fragmentation and appearance in the cytosol or extracellular spaces signals several pro-inflammatory pathways.  The mechanism(s) responsible for mitochondrial extrusion are not completely understood, however, the mitochondrial evolutionary bridge to bacteria enables certain pathogen-associated molecular pattern receptors of the innate immune system to produce pro-inflammatory molecules. These systems include (but are not limited to); TLR9 (Toll-like receptor 9), NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor-3), and the DNA sensor, cGAS (cyclic GMP-AMP synthase).  TLR9 which is found mostly in macrophages recognizes the cytidine-phosphate-guanine motifs of mtDNA which are in common with bacteria and viruses. As a result, TLR9 activates the NF-kB pathway which induces pro-inflammatory genes such as TNFa (tumor necrosis factor). TNFa induces neuronal cell death. Thus, mtDNA serves as an immune platform. Moreover, mtDNA maintenance 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.