Obesity‑related inflammation creates oxidative stress that harms mitochondria, leading to insulin resistance and type‑2 diabetes. Damage to mitochondrial DNA and proteins reduces energy production and raises harmful ROS. Boosting mitochondrial health—by protecting DNA, supporting biogenesis, or using mitochondrial‑derived peptides—could help counteract these effects, but concrete dosing or protocols aren’t yet defined.

One reason for the development of insulin resistance is the chronic inflammation in obesity. Scientific articles in the field of knowledge on the involvement of mitochondria and mitochondrial DNA (mtDNA) in obesity and type 2 diabetes were analyzed. Oxidative stress developed during obesity contributes to the formation of peroxynitrite, which causes cytochrome C-related damage in the mitochondrial electron transfer chain and increases the production of reactive oxygen species (ROS), which is associated with the development of type 2 diabetes. Oxidative stress contributes to the nuclease activity of the mitochondrial matrix, which leads to the accumulation of cleaved fragments and an increase in heteroplasmy. Mitochondrial dysfunction and mtDNA variations during insulin resistance may be connected with a change in ATP levels, generation of ROS, mitochondrial division/fusion and mitophagy. This review discusses the main role of mitochondria in the development of insulin resistance, which leads to pathological processes in insulin-dependent tissues, and considers potential therapeutic directions based on the modulation of mitochondrial biogenesis. In this regard, the development of drugs aimed at the regulation of these processes is gaining attention. Changes in the mtDNA copy number can help to protect mitochondria from severe damage during conditions of increased oxidative stress. Mitochondrial proteome studies are conducted to search for potential therapeutic targets. The use of mitochondrial peptides encoded by mtDNA also represents a promising new approach to therapy.