Mitochondrial dysfunction as a probable mechanism for triggering inflammatory joint diseases

The article concerns the contribution of mitochondrial dysfunction to the development of inflammatory joint diseases. Mitochondria are the main suppliers of adenosine triphosphate (ATP). Reactive oxygen species (ROS) are a by-product of this metabolic process. Mitochondria also have an effective antioxidant mechanism: there is a certain balance between the ROS formation and their inactivation. Accumulation with age of mutations (single nucleotide substitutions, e.g., transversions, transitions, and deletions) in mitochondrial DNA, may cause a disorder in selective destruction (utilization) of damaged and dysfunctional mitochondria (mitophagy) thus leading to imbalance between the ROS production and their neutralization. This process is triggered by both internal factors (ROS overproduction) and external factors, i.e., tissue damage / injury and infection. The failure of quality control mechanisms resulting from disruption of mitophagy leads to a significant increase in terminally damaged mitochondria, which become a threat to cell survival. High level of genetic mutations accumulating with age in mitochondrial genome causes an increased formation of ROS, which, in turn, are one of the leading activators of the cytosolic NLRP3 protein, the main component of inflammasome type of the same name. Increased inflammasome formation ultimately triggers caspase-1 dependent production of pro-inflammatory interleukins-1β (IL-1β) and 18 (IL-18). Inadequate removal of damaged mitochondria leads to hyperactivation of inflammatory signaling pathways and, subsequently, to chronic systemic inflammation and development of inflammatory diseases, including primary osteoarthritis (OA). To assess the level of mitochondrial dysfunction, we assessed the numbers of mitochondrial genome copies in post-mitotic muscle cells in 48 patients aged 45 to 95 years who were diagnosed with OA of the knee or hip joints. As a result of our study, we have discovered and confirmed some regularities of human mtDNA mutations corresponding to those in vertebrates, and, in particular, in mammals. Degenerate mutation spectra (without classification of mutations by mtDNA chains and the context of surrounding nucleotides) were constructed for mtDNA in general, and for each individual sample. It was demonstrated that, in one-third of muscle samples, the critical threshold of mtDNA heteroplasmy was exceeded, at which the aberrant biochemical phenotype, in terms of oxidative phosphorylation functioning, (OXPHOS) becomes dominant. Of note, the heteroplasmy rates are lower in older patients who have had significant physical activity during their lives (sports, moderate physical work, etc.). Moreover, the heteroplasmy showed an inverse correlation with high mtDNA copy number. The results obtained can be used to diagnose pathologies in elderly, and the process of healthy aging.