Mitochondrial Reactive Oxygen Species, Insulin Resistance, and Nrf2-Mediated Oxidative Stress Response-Toward an Actionable Strategy for Anti-Aging

Reactive oxygen species (ROS) are produced mainly by mitochondrial respiration and function as signaling molecules in the physiological range. However, ROS production is also associated with the pathogenesis of various diseases, including insulin resistance (IR) and type 2 diabetes (T2D). This review focuses on the etiology of IR and early events, especially mitochondrial ROS (mtROS) production in insulin-sensitive tissues. Importantly, IR and/or defective adipogenesis in the white adipose tissues (WAT) is thought to increase free fatty acid and ectopic lipid deposition to develop into systemic IR. Fatty acid and ceramide accumulation mediate coenzyme Q reduction and mtROS production in IR in the skeletal muscle, while coenzyme Q synthesis downregulation is also involved in mtROS production in the WAT. Obesity-related IR is associated with the downregulation of mitochondrial catabolism of branched-chain amino acids (BCAAs) in the WAT, and the accumulation of BCAA and its metabolites as biomarkers in the blood could reliably indicate future T2D. Transcription factor NF-E2-related factor 2 (Nrf2), which regulates antioxidant enzyme expression in response to oxidative stress, is downregulated in insulin-resistant tissues. However, Nrf2 inducers, such as sulforaphane, could restore Nrf2 and target gene expression and attenuate IR in multiple tissues, including the WAT.

Automated summary

This review focuses on the etiology of insulin resistance and early events, particularly the production of mitochondrial ROS in insulin-sensitive tissues. It highlights the association of insulin resistance with defects in adipogenesis in white adipose tissues, fatty acid and ceramide accumulation, and downregulation of mitochondrial catabolism. The review also discusses the role of NF-E2-related factor 2 in regulating antioxidant enzyme expression and how its downregulation is involved in insulin resistance. Finally, it explores the potential of Nrf2 inducers in restoring Nrf2 and attenuating insulin resistance.