Mitochondrial Mechanisms Link Oxidative Stress and Chronic Inflammation
Aging is characterized by rising levels of oxidative stress, the presence of oxidative molecules and the damage they cause to molecular machinery in cells, and rising levels of chronic inflammation, an inappropriate and harmful overactivation of the immune system. It is noted that these two aspects of aging and age-related disease appear to go hand in hand, when one is elevated, so is the other. Why is this the case?
The obvious place to start any such investigation is the mitochondrion. Every cell is populated by hundreds of mitochondria, responsible for packaging chemical energy store molecules in a process that produces reactive oxygen species (ROS) as a byproduct. While the cell uses ROS production as a signaling mechanism under normal circumstances, dysfunctional mitochondria produce too great a flux of ROS. Equally, mitochondria are also involved in many other vital cellular processes. For example, there are well-mapped pathways of protein interactions that lead directly from mitochondrial activity to the activation of inflammatory signaling on the part of their host cell.
This is the explanation for the observation that inflammatory disease is accompanied by oxidative stress, and the ability of mitochondrially targeted antioxidants such as SkQ1 to succeed as a treatment for inflammatory eye conditions. Preventing excessive ROS leaving mitochondria helps to dampen signaling processes that lead to inflammation. Reducing inflammation helps tissues to recover at least somewhat from the disease state.
Neurodegenerative diseases have certain characteristics in common. These include a state of inflammation and impaired elimination of defective mitochondrial organelles. Researchers now report their investigation of mice that have alterations in genes linked to Parkinson's disease. The authors identify a direct connection between the cellular process that eliminates damaged mitochondria - called mitophagy - and inflammation.
The enzymes PINK1 and parkin act in a pathway that attaches a protein called ubiquitin to cellular proteins; such ubiquitin-tagged components are targeted for cellular destruction. These enzymes assist with the process of mitophagy, in which non-functional mitochondrial fragments are recycled. Mutations that prevent the normal expression of PINK1 or parkin are linked to an early-onset form of Parkinson's disease, and there is evidence that failure to successfully eliminate damaged mitochondria results in a higher risk of developing the disease. However, mice that are deficient in PINK1 or parkin do not develop symptoms.
The finding that the loss of PINK1 or parkin has a minimal effect on animals was surprising, because it was long thought that the removal of damaged mitochondria serves a key role in protecting cells from oxidative damage. Defective mitochondria represent a severe threat to cells because ruptured mitochondria might release reactive oxygen species (ROS) that cause substantial cellular damage. Defective mitochondria might also release components that are not normally present in the cytoplasm, such as mitochondrial DNA. Indeed, the intrusion of mitochondrial DNA into the cytoplasm can trigger inflammation mediated by the protein STING. This raises the question of whether protection from inflammation, rather than from oxidative damage, might be the key role of mitophagy in the context of Parkinson's disease.
When researchers imposed mitochondrial stress on animals lacking PINK1 or parkin, they found that the bloodstream level of inflammation-driving molecules called cytokines was much higher than it was in mice that were not subjected to this mitochondrial stress. However, if mice lacked STING, as well as PINK1 or parkin, the expression of inflammatory cytokines did not increase as a result of mitochondrial stress. This indicated that STING is required to drive the inflammation mediated by this type of stress. Moreover, an absence of STING prevented the movement defects and neuronal losses that usually occur in old mitochondrial mutator mice that lack parkin.