Mitochondrial DNA and Inflammation
Maintaining the integrity of mtDNA is a vitally important mechanism to counter chronic inflammation and organ damage in many diseases of aging without limiting immune system responses to infection or injury. Inflammation, an early immune response to microbial infection, is stimulated by chemical factors released by injured cells. This response establishes a physical barrier against further spread of infection and promotes healing of any damaged tissue following the clearance of pathogens. Inflammation is initiated by cells residing in tissues, mainly macrophages, dendritic cells, mast cells and others. On the surface, or within these cells, are receptors, named pattern recognition receptors (PRRs), such as the Toll Like Receptors (TLRs), which recognize molecular characteristics, collectively referred to as pathogen associated molecular patterns (PAMPs), that are broadly shared by pathogens but distinguishable from host molecules. At the onset of an infection, burn, or other injuries, these cells are activated when one of the PRRs on the cell recognizes a PAMP. This results in the release of multiple inflammatory mediators called cytokines, e.g., tumor necrosis factor-a. These cytokines are responsible for the clinical signs of inflammation.
Proteins or nucleic acid sequences of bacterial RNA or DNA serve as immuno-stimulatory agents. Similarly, human cells release molecules, e.g., pieces of genomic DNA, called damage-associated molecular patterns, (DAMPS) which arise from cell damage or death to stimulate cytokine release for resolution of cell injury. Perhaps owing to the bacterial origin of mitochondria, mtDNA shares nucleic acid sequences that cells recognize as foreign molecules. These molecules engage the immune system. The cytosine phosphodiester guanine (CpG) motif of mtDNA provides a recognition signal similar to that found in bacterial DNA, thereby promoting PRR activation.
Oxidative damage to mtDNA is a common feature of cellular stress or death, microbial infection and inflammatory diseases. Mitochondria, under periods of stress or injury, release oxidized fragments into the cytosol, the extracellular space, and the systemic circulation. These ejected mtDNA fragments are immuno-stimulatory and trigger activation of multiple pro-inflammatory pathways that contribute to chronic inflammation including TLR9, cGas-Sting, inflammasome formation and others. As a result, mtDNA may serve as a molecular sentinel linking oxidative stress to numerous sources of inflammation and cell death. Injecting mtDNA, or its corollary CpG motifs, directly into tissue, causes inflammation and cell death. This has been demonstrated in studies of arthritis and neurodegeneration. In both cases, the mtDNA-TLR9 receptor interaction initiated the inflammatory cascade. Maintaining the integrity of mtDNA, therefore, is a vitally important mechanism to counter inflammation in diseases of aging.