Lim Sangbin, Rashid Md Abdur, Jang Miran, Kim Yeonghwan, Won Hyeran, Lee Jeonghoon, Woo Jeong-taek, Kim Young Seol, Murphy Michael P, Ali Liaquat, Ha Joohun, Kim Sung Soo
Department of Biochemistry and Molecular Biology, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute (BK-21), School of Medicine, Kyung Hee University, Seoul, Korea.
Cell Physiol Biochem. 2011;28(5):873-86. doi: 10.1159/000335802. Epub 2011 Dec 15.
Mitochondrial oxidative damage is thought to play a key role in pancreatic β-cell failure in the pathogenesis of type 2 diabetes. Despite this, the potential of mitochondria-targeted antioxidants to protect pancreatic β-cells against oxidative stress has not yet been studied. Therefore, we investigated if mitochondria-targeted antioxidants protect pancreatic β-cells such as RINm5F and HIT-T15 cells against oxidative stress under glucotoxic and glucolipotoxic conditions. When β-cells were incubated under these conditions, the expression levels of mitochondrial electron transport chain complex subunits, mitochondrial antioxidant enzymes (such as MnSOD and Prx3), β-cell apoptosis, lipogenic enzymes (such as ACC, FAS and ABCA1), intracellular lipid accumulation, oxidative stress, ER stress, mitochondrial membrane depolarization, nuclear NF- κB and sterol regulatory element binding protein 1c (SREBP1c) were all increased, in parallel with decreases in intracellular ATP content, citrate synthase enzymatic activity and glucose-stimulated insulin secretion. These changes were consistent with elevated mitochondrial oxidative stress, and incubation with the mitochondria-targeted antioxidants, MitoTempol or Mitoquinone (MitoQ), prevented these effects. In conclusion, mitochondria-targeted antioxidants protect pancreatic β-cells against oxidative stress, promote their survival, and increase insulin secretion in cell models of the glucotoxicity and glucolipotoxicity associated with Type 2 diabetes.
线粒体氧化损伤被认为在2型糖尿病发病机制中的胰腺β细胞功能衰竭中起关键作用。尽管如此，线粒体靶向抗氧化剂保护胰腺β细胞免受氧化应激的潜力尚未得到研究。因此，我们研究了线粒体靶向抗氧化剂是否能在糖毒性和糖脂毒性条件下保护胰腺β细胞，如RINm5F和HIT-T15细胞免受氧化应激。当β细胞在这些条件下孵育时，线粒体电子传递链复合物亚基、线粒体抗氧化酶（如MnSOD和Prx3）、β细胞凋亡、脂肪生成酶（如ACC、FAS和ABCA1）、细胞内脂质积累、氧化应激、内质网应激、线粒体膜去极化、核NF-κB和固醇调节元件结合蛋白1c（SREBP1c）的表达水平均升高，同时细胞内ATP含量、柠檬酸合酶酶活性和葡萄糖刺激的胰岛素分泌降低。这些变化与线粒体氧化应激升高一致，而用线粒体靶向抗氧化剂MitoTempol或Mitoquinone（MitoQ）孵育可防止这些影响。总之，线粒体靶向抗氧化剂在与2型糖尿病相关的糖毒性和糖脂毒性细胞模型中保护胰腺β细胞免受氧化应激，促进其存活，并增加胰岛素分泌。
