Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1 α axis improves mitochondrial biogenesis and glucose catabolism

In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.PMID:33794310 | DOI:10.1016/j.freeradbiomed.2021.03.029

Source: Free Radical Biology and Medicine - April 1, 2021 Category: Biology Authors: Meiling Wu Chunwang Zhang Mengdan Xie Yuansheng Zhen Ben Lai Jiankang Liu Liang Qiao Shanlin Liu Dongyun Shi Source Type: research