Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

Inflammation is a natural reaction of the innate immune system that evolved primarily to protect the human body from invading pathogens and to heal injuries. There are two different types of inflammation, acute and chronic inflammation, differing in duration, underlying causes, and characteristics. The acute-to-chronic transition can be determined by several pathomech-anisms, including dysregulation of immune response and failure to eliminate the underlying cause. Moreover, epigenetic changes that refer to modifications in gene expression that are heritable but do not involve changes to the underlying DNA sequence can also contribute to prolonged inflammation. Emerging evidence suggests that dysfunctional mitochondria can promote the development of chronic inflammation. In this respect, the mechanisms triggering defective mitophagy, a selective form of autophagy that exterminates dysfunctional mitochondria to maintain cellular homeostasis, attracted special attention. The hypothesis on the pivotal role of mutations in mitochondrial DNA causing defective mitophagy stimulated the area of the research that applies editing of the mitochondrial genome. The mitoCAS9 vector and two single guide RNAs to the G15059A mutation were used to eliminate the mutation from the macrophage-like cells. The normal activity of the initially defective mitophagy was restored in intact macrophage-like cells, confirming the causal role of the G15059A mutation in the disruption of the mitophagy process. The unraveling of the underlying mechanisms of chronic inflammation will help to develop targeted therapeutic approaches aimed at restoring mitochondrial health and alleviating chronic inflammation that can be used for the treatment of a wide range of chronic inflammatory diseases.