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Mitochondrial Reactive Oxygen Species, Insulin Resistance, and Nrf2-Mediated Oxidative Stress Response-Toward an
Shuya Kasai1, Daichi Kokubu2,3, Hiroki Mizukami4
1Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
Abstract:
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.
Insights
Mitochondrial reactive oxygen species (ROS) contribute to insulin resistance (IR) and type 2 diabetes (T2D). Targeting Nrf2 with inducers like sulforaphane may restore insulin sensitivity.
Area of Science:
- Biochemistry
- Metabolism
- Cellular Biology
Background:
- Reactive oxygen species (ROS) are crucial signaling molecules but also implicated in diseases like insulin resistance (IR) and type 2 diabetes (T2D).
- Mitochondrial ROS (mtROS) production is a key factor in the early stages of IR development across various tissues.
Purpose of the Study:
- To review the etiology of IR and the role of mtROS in insulin-sensitive tissues.
- To explore the connection between defective adipogenesis, lipid accumulation, and systemic IR.
- To examine the impact of branched-chain amino acid (BCAA) metabolism and Nrf2 signaling in IR.
Main Methods:
- Review of existing literature on ROS, mitochondrial function, and metabolic diseases.
- Analysis of the mechanisms linking fatty acid and ceramide accumulation to mtROS production.
- Investigation of the role of BCAA catabolism and Nrf2 pathway in white adipose tissue (WAT) dysfunction.
Main Results:
- Fatty acid and ceramide accumulation in skeletal muscle and reduced coenzyme Q synthesis in WAT contribute to mtROS production in IR.
- Obesity-related IR is linked to impaired BCAA catabolism in WAT, with elevated BCAAs as potential T2D biomarkers.
- Downregulation of the transcription factor Nrf2 is observed in insulin-resistant tissues.
Conclusions:
- mtROS play a significant role in the pathogenesis of IR and T2D.
- Nrf2 inducers, such as sulforaphane, show potential in restoring Nrf2 activity and ameliorating IR in multiple tissues, including WAT.
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