Mitochondrial dysfunction and glucose uptake

Mitochondria play a central role in cellular energy production and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A, stimulated Glut1-mediated glucose uptake without altering Glut1 mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxia-telangiectasia mutated (ATM; a potential AMPK kinase), Src (previously highlighted to stimulate Glut1-mediated glucose uptake), and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin A- and antimycin A-treated cells), appeared not to be involved in glucose uptake simulation. Inhibitor treatment increased NAD+ and NADH levels (leading to a lower NAD+/NADH ratio), but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced upon inhibition of Sirt2 or mTOR/RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of Akt/mTOR/RAPTOR and Glut1-mediated glucose uptake.