Basal autophagy induction without AMP-activated protein kinase under low glucose conditions.
When ATP levels in a cell decrease, various homeostatic intracellular mechanisms initiate attempts to restore ATP levels. As a prominent energy sensor, AMP-activated protein kinase (AMPK) represents one molecular gauge that links energy levels to regulation of anabolic and catabolic processes to restore energy balance. Although pharmacological studies have suggested that an AMPK activator, AIC AR (5-aminoimidazole-4-carboxamide ribonucleoside) may link AMPK activation to autophagy, a process that can provide short-term energy within the cell, AICAR can have AMPK-independent effects. Therefore, using a genetic-based approach we investigated the role of AMPK in cellular energy balance. We demonstrate that genetically altered cells, mouse embryonic fibroblasts (MEFs), lacking functional AMPK, display altered energy balance under basal conditions and die prematurely under low glucose-serum starvation challenge. These AMPK mutant cells appear to be abnormally reliant on autophagy under low glucose basal conditions, and therefore cannot rely further on autophagy like wild-type cells during further energetic stress and instead undergo apoptosis. This data suggests that AMPK helps regulate basal energy levels under low glucose. Further, AMPK mutant cells show increased basal phosphorylation of p53 at serine 15, a residue phosphorylated under glucose deprivation. We propose that cells lacking AMPK function have altered p53 activity that may help sensitize these cells to apoptosis under energetic stress.
The Neuroscience Center UNC Chapel Hill School of Medicine, USA.
Tyisha
T
Williams
Lawrence J
LJ
Forsberg
Benoit
B
Viollet
Jay E
JE
Brenman
D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D016895:Culture Media, Serum-Free; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005947:Glucose / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016895:Culture Media, Serum-Free; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; C025946:3-methyladenine; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose; D000225:Adenine