In a new study, researchers have identified a direct link between mitophagy and inflammation.
Aging is accompanied by rising levels of oxidative stress, which is primarily caused by our cellular power plants, the mitochondria. As we age, our mitochondria start to produce an increasing amount of oxidized molecules known as reactive oxygen species (ROS), which bounce around our cells and can damage their components. ROS strikes can delete sections of mitochondrial DNA (mtDNA), damage other cellular machinery, increase inflammation, and spur inappropriate immune system responses.
Under normal conditions, as our mitochondria synthesize ATP, the fuel that allows our cells to function, they also produce a small amount of ROS as a byproduct. ROS is used as a signaling mechanism and perform a vital cellular function, so their presence is critical; however, as we age, more and more of our mitochondria become dysfunctional and enter an aberrant state in which they produce less ATP and create more ROS, upsetting the delicate balance of our cells.
Mitochondria are also critical for a variety of other cellular functions, including protein interactions that link mitochondrial activity to the activation of pro-inflammatory signaling in the cell.
The new study shows the connection between mitophagy, how cells dispose of dysfunctional mitochondria, and inflammation, and it explains why inflammatory diseases are accompanied by oxidative stress .
Although serum from patients with Parkinson’s disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson’s disease. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson’s-disease-relevant phenotypes. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity, suggesting that mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Prkn−/− and Pink1−/− mice following exhaustive exercise and in Prkn−/−;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA). Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn−/−;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity.
Researchers in this new study has shown a direct link between inflammatory disease and oxidative stress. Because antioxidants like SkQ1 reduce ROS levels in the mitochondria and thus prevent inflammation, they have been successful in treating inflammatory eye conditions.
These researchers are thinking in terms of blocking STING-dependent inflammation, but treating the problem at the source is a better long-term goal.
If excessive ROS levels can be mitigated by reducing the frequency of mtDNA damage through protecting this DNA within the nucleus, this technique could help prevent age-related inflammation spurred by excessive ROS. This is why mitochondrial repair approaches such as MitoSENS offer a potential avenue for heading age-related diseases off at the pass: they address the issue of excessive ROS generation at the source.
 Sliter, D. A., Martinez, J., Hao, L., Chen, X., Sun, N., Fischer, T. D., … & Cai, H. (2018). Parkin and PINK1 mitigate STING-induced inflammation. Nature.