AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest

• Published in: Nature cell biology Vol. 17; no. 10; pp. 1304 - 1316
• Main Authors: Doménech, Elena, Maestre, Carolina, Esteban-Martínez, Lorena, Partida, David, Pascual, Rosa, Fernández-Miranda, Gonzalo, Seco, Esther, Campos-Olivas, Ramón, Pérez, Manuel, Megias, Diego, Allen, Katherine, López, Miguel, Saha, Asish K., Velasco, Guillermo, Rial, Eduardo, Méndez, Raúl, Boya, Patricia, Salazar-Roa, María, Malumbres, Marcos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2015; Nature Publishing Group
• Subjects: 13/2; 13/89; 14/28; 14/33; 38/77; 42/35; 631/80/641/1655; 631/80/642/333/1465; 631/80/82/23; 631/80/86; 64/60; 82/80; 96/106; 96/109; 96/31; 96/34; 96/63; 96/95; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Autophagy - genetics; Autophagy - physiology; Blotting, Western; Cancer; Cancer Research; Care and treatment; Cdc20 Proteins - genetics; Cdc20 Proteins - metabolism; Cell Biology; Cell Line, Tumor; Cell metabolism; Cell Survival - drug effects; Cell Survival - genetics; Cell Survival - physiology; Cells, Cultured; Developmental Biology; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Enzymes; Female; Fibroblasts - metabolism; Fibroblasts - ultrastructure; Genetic aspects; Glycolysis; Humans; Life Sciences; M Phase Cell Cycle Checkpoints - genetics; M Phase Cell Cycle Checkpoints - physiology; MCF-7 Cells; Methods; Mice, Knockout; Mice, Nude; Microscopy, Confocal; Mitosis; Molecular targeted therapy; Paclitaxel - pharmacology; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; Poisons; Regulation; RNA Interference; Stem Cells; Xenograft Model Antitumor Assays
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3231

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells. Malumbres and colleagues reveal that mitotic arrest is accompanied by reduced mitochondrial mass and oxidative respiration resulting in activation of AMPK and induction of glycolysis to promote cell survival.