title: Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR-RAPTOR.
abstract: 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 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxia-telangiectasia mutated (ATM; a potential AMPK kinase) and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin-A- and antimycin-A-treated cells) appeared not to be involved in the stimulation of glucose uptake. Treatment with mitochondrial inhibitors increased NAD+and NADH levels (associated with a lower NAD+:NADH ratio) but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced by chemical inhibition of Sirt2 or mTOR-RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of mTOR-RAPTOR and Glut1-mediated glucose uptake.
authors: Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Centre for Systems Biology and Bioenergetics, Radboud University and Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
authors: Dania C
authors: 0000-0002-6744-0161
authors: DC
authors: Liemburg-Apers
authors: Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Centre for Systems Biology and Bioenergetics, Radboud University and Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
authors: Jori A L
authors: JA
authors: Wagenaars
authors: Centre for Systems Biology and Bioenergetics, Radboud University and Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
authors: Jan A M
authors: 0000-0003-1392-8038
authors: JA
authors: Smeitink
authors: Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Centre for Systems Biology and Bioenergetics, Radboud University and Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
authors: Peter H G M
authors: 0000-0002-0915-1599
authors: PH
authors: Willems
authors: Department of Biochemistry (286), Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands werner.koopman@radboudumc.nl.|Centre for Systems Biology and Bioenergetics, Radboud University and Radboud University Medical Center, 6500HB, Nijmegen, The Netherlands.|Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525GA, Nijmegen, The Netherlands.
authors: Werner J H
authors: 0000-0002-5340-6747
authors: WJ
authors: Koopman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D056565:Sirtuin 2 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D051272:Glucose Transporter Type 1; D017382:Reactive Oxygen Species; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D056565:Sirtuin 2; D005947:Glucose
keywords: Acetylation; Antimycin A; Glucose; NADH; Piericidin A