Transgenic type2 diabetes mouse models for in vivo redox measurement of hepatic mitochondrial oxidative stress

• Published in: Biochimica et biophysica acta. General subjects Vol. 1867; no. 3; p. 130302
• Main Authors: Kamimura, Naomi, Wolf, Alexander M., Yokota, Takashi, Nito, Chikako, Takahashi, Hiroshi, Ohta, Shigeo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2023
• Subjects: Animals; Biosensing technique; Diabetes; Diabetes Mellitus, Type 2 - genetics; Disease model; Liver; Mice; Mice, Transgenic; Mitochondria; Oxidation-Reduction; Oxidative Stress; APAP; Oxidative stress; MPC; NAFLD; Liver; CoQ10; OXPHOS; Biosensing technique; roGFP; NF-κB; SD; Mitochondria; GSH; AGE; 8-OHdG; PBS; PKC; RAGE; DAG; PPARγ; NAD; ROS; AMPK; Diabetes; Disease model
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130302

Oxidative stress is involved in the progression of diabetes and its associated complications. However, it is unclear whether increased oxidative stress plays a primary role in the onset of diabetes or is a secondary indicator caused by tissue damage. Previous methods of analyzing oxidative stress have involved measuring the changes in oxidative stress biomarkers. Our aim is to identify a novel approach to clarify whether oxidative stress plays a primary role in the onset of diabetes. We constructed transgenic type 2 diabetes mouse models expressing redox-sensitive green fluorescent proteins (roGFPs) that distinguished between mitochondria and whole cells. Pancreas, liver, skeletal muscle, and kidney redox states were measured in vivo. Hepatic mitochondrial oxidation increased when the mice were 4 weeks old and continued to increase in an age-dependent manner. The increase in hepatic mitochondrial oxidation occurred simultaneously with weight gain and increased blood insulin levels before the blood glucose levels increased. Administering the oxidative stress inducer acetaminophen increased the vulnerability of the liver mitochondria to oxidative stress. This study demonstrates that oxidative stress in liver mitochondria in mice begins at the onset of diabetes rather than after the disease has progressed. RoGFP-expressing transgenic type 2 diabetes mouse models are effective and convenient tools for measuring hepatic mitochondrial redox statuses in vivo. These models may be used to assess mitochondria-targeting antioxidants and establish the role of oxidative stress in type 2 diabetes. •Type 2 diabetes mouse models with redox biosensors were generated.•Oxidative stress was observed in liver mitochondria in early-stage diabetes.•Liver mitochondria in diabetic mice are vulnerable to oxidative stress.