AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: Implication of the cell survival in mitochondrial diseases

作者：Wu Shi Bei; Wei Yau Huei^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2012, 1822(2): 233-247.

DOI：10.1016/j.bbadis.2011.09.014

• Mitochondrial disease
• MERRF syndrome
• Oxidative stress
• AMPK
• Glycolysis
• NADPH

We report that the energy metabolism shifts to anaerobic glycolysis as an adaptive response to oxidative stress in the primary cultures of skin fibroblasts from patients with MERRF syndrome. In order to unravel the molecular mechanism involved in the alteration of energy metabolism under oxidative stress, we treated normal human skin fibroblasts (CCD-966SK cells) with sub-lethal doses of H2O2. The results showed that several glycolytic enzymes including hexokinase type II (HK II), lactate dehydrogenase (LDH) and glucose transporter 1 (GLUT1) were up-regulated in H2O2-treated normal skin fibroblasts. In addition, the glycolytic flux of skin fibroblasts was increased by H2O2 in a dose-dependent manner through the activation of AMP-activated protein kinase (AMPK) and phosphorylation of its downstream target, phosphofructokinase 2 (PFK2). Moreover, we found that the AMPK-mediated increase of glycolytic flux by H2O2 was accompanied by an increase of intracellular NADPH content By treatment of the cells with glycolysis inhibitors, an AMPK inhibitor or genetic knockdown of AMPK, respectively, the H2O2-induced increase of NADPH was abrogated leading to the overproduction of intracellular ROS and cell death. Significantly, we showed that phosphorylation levels of AMPK and glycolysis were up-regulated to confer an advantage of survival for MERRF skin fibroblasts. Taken together, our findings suggest that the increased production of NADPH by AMPK-mediated increase of the glycolytic flux contributes to the adaptation of MERRF skin fibroblasts and H2O2-treated normal skin fibroblasts to oxidative stress.

• 出版日期2012-2