Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

AMPK: guardian of metabolism and mitochondrial homeostasis

Key Points

  • AMP-activated protein kinase (AMPK) is a highly conserved sensor of low intracellular ATP levels that is rapidly activated after nearly all mitochondrial stresses, even those that do not disrupt the mitochondrial membrane potential.

  • Upon changes in the ATP-to-AMP ratio, AMPK is activated and phosphorylates downstream targets to redirect metabolism towards increased catabolism and decreased anabolism.

  • AMPK regulates autophagy and mitophagy through activation of the kinase ULK1, the mammalian homologue of ATG1.

  • AMPK phosphorylates mitochondrial fission factor and promotes mitochondrial fission upon energetic stress.

  • By simultaneously regulating mitochondrial fission, mitophagy and transcriptional control of mitochondrial biogenesis, AMPK acts as a signal integration platform to maintain mitochondrial health.

  • AMPK also controls transcriptional regulators of autophagy and lysosomal genes.

Abstract

Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AMPK structure and activation.
Figure 2: AMPK regulates a variety of metabolic processes.
Figure 3: Regulation of mitochondrial homeostasis by AMPK.
Figure 4: Details of the regulation of autophagy by mTOR, AMPK and ULK1.
Figure 5: Modulation of the transcription of autophagy and lysosome genes by AMPK.

Similar content being viewed by others

References

  1. Celenza, J. L. & Carlson, M. A yeast gene that is essential for release from glucose repression encodes a protein kinase. Science 233, 1175–1180 (1986).

    Article  CAS  PubMed  Google Scholar 

  2. Gancedo, J. M. Carbon catabolite repression in yeast. Eur. J. Biochem. 206, 297–313 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Crozet, P. et al. Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases. Front. Plant Sci. 5, 190 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Inoki, K., Zhu, T. & Guan, K.-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Carling, D., Zammit, V. A. & Hardie, D. G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 223, 217–222 (1987).

    Article  CAS  PubMed  Google Scholar 

  7. Munday, M. R., Campbell, D. G., Carling, D. & Hardie, D. G. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem. 175, 331–338 (1988).

    Article  CAS  PubMed  Google Scholar 

  8. Watt, M. J. et al. Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am. J. Physiol. Endocrinol. Metab. 290, E500–E508 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Ahmadian, M. et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 13, 739–748 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Marsin, A. S. et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10, 1247–1255 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Bando, H. et al. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6- bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Clin. Cancer Res. 11, 5784–5792 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Sakamoto, K. & Holman, G. D. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab. 295, E29–E37 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu, N. et al. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol. Cell 49, 1167–1175 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Toyama, E. Q. et al. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016). This study identifies AMPK as necessary and sufficient to rapidly promote mitochondrial fission in response to ETC inhibitors and identifies the DRP1 receptor MFF as a direct substrate of AMPK involved in this process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zong, H. et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl Acad. Sci. USA 99, 15983–15987 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jäger, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang, W. et al. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J. Biol. Chem. 276, 38341–38344 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Koo, S.-H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bungard, D. et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201–1205 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, Y. et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13, 376–388 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mihaylova, M. M. et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607–621 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shin, H.-J. R. et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534, 553–557 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Young, N. P. et al. AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes. Genes Dev. 30, 535–552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hoffman, N. J. et al. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. Cell Metab. 22, 922–935 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ducommun, S. et al. Motif affinity and mass spectrometry proteomic approach for the discovery of cellular AMPK targets: identification of mitochondrial fission factor as a new AMPK substrate. Cell. Signal. 27, 978–988 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Schaffer, B. E. et al. Identification of AMPK phosphorylation sites reveals a network of proteins involved in cell invasion and facilitates large-scale substrate prediction. Cell Metab. 22, 907–921 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hardie, D. G., Schaffer, B. E. & Brunet, A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 26, 190–201 (2016). This review comprehensively examines all reported AMPK substrates up to late 2016, annotating phosphorylation sites and criteria met to support classification as a substrate.

    Article  CAS  PubMed  Google Scholar 

  31. Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45, 31–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Stapleton, D. et al. Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem. 271, 611–614 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Thornton, C., Snowden, M. A. & Carling, D. Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle. J. Biol. Chem. 273, 12443–12450 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Cheung, P. C., Salt, I. P., Davies, S. P., Hardie, D. G. & Carling, D. Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem. J. 346, 659–669 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ross, F. A., MacKintosh, C. & Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours. FEBS J. 283, 2987–3001 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hudson, E. R. et al. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13, 861–866 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Xiao, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Hardie, D. G., Carling, D. & Gamblin, S. J. AMP-activated protein kinase: also regulated by ADP? Trends Biochem. Sci. 36, 470–477 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Gowans, G. J., Hawley, S. A., Ross, F. A. & Hardie, D. G. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 18, 556–566 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ross, F. A., Jensen, T. E. & Hardie, D. G. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem. J. 473, 189–199 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Hawley, S. A. et al. 5′-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J. Biol. Chem. 270, 27186–27191 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Suter, M. et al. Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281, 32207–32216 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Oakhill, J. S. et al. β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc. Natl Acad. Sci. USA 107, 19237–19241 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Davies, S. P., Helps, N. R., Cohen, P. T. & Hardie, D. G. 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2Cα and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421–425 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Birk, J. B. & Wojtaszewski, J. F. P. Predominant α2/β2/γ3 AMPK activation during exercise in human skeletal muscle. J. Physiol. 577, 1021–1032 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jensen, T. E. et al. PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle, but activates all three γ subunit complexes in cultured human cells by inhibiting the respiratory chain. Biochem. J. 467, 461–472 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Rajamohan, F. et al. Probing the enzyme kinetics, allosteric modulation and activation of α1- and α2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem. J. 473, 581–592 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. McGee, S. L. et al. Exercise increases nuclear AMPKα2 in human skeletal muscle. Diabetes 52, 926–928 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Suzuki, A. et al. Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the α2 form of AMP-activated protein kinase. Mol. Cell. Biol. 27, 4317–4327 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pinter, K., Grignani, R. T., Watkins, H. & Redwood, C. Localisation of AMPK γ subunits in cardiac and skeletal muscles. J. Muscle Res. Cell Motil. 34, 369–378 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liang, J. et al. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat. Commun. 6, 7926 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Zhang, Y.-L. et al. AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation. Cell Metab. 18, 546–555 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Zhang, C.-S. et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab. 20, 526–540 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Zhang, C.-S. et al. Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548, 112–116 (2017). This study discovers a provocative new AMP-independent mechanism for glucose sensing by AMPK that involves a super-complex of LKB1, axin, AMPK, the LAMTOR–Ragulator complex and the glycolytic enzyme aldolase on the surface of the lysosome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Alessi, D. R., Sakamoto, K. & Bayascas, J. R. LKB1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137–163 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Ikeda, Y. et al. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J. Biol. Chem. 284, 35839–35849 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jessen, N. et al. Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function. Biochim. Biophys. Acta 1802, 593–600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shan, T., Zhang, P., Bi, P. & Kuang, S. Lkb1 deletion promotes ectopic lipid accumulation in muscle progenitor cells and mature muscles. J. Cell. Physiol. 230, 1033–1041 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ollila, S. & Mäkelä, T. P. The tumor suppressor kinase LKB1: lessons from mouse models. J. Mol. Cell. Biol. 3, 330–340 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hurley, R. L. et al. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060–29066 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Woods, A. et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21–33 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Marcelo, K. L., Means, A. R. & York, B. The Ca2+/calmodulin/CaMKK2 axis: nature's metabolic CaMshaft. Trends Endocrinol. Metab. 27, 706–718 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Yang, Y., Atasoy, D., Su, H. H. & Sternson, S. M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tamás, P. et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203, 1665–1670 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Stahmann, N., Woods, A., Carling, D. & Heller, R. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase β. Mol. Cell. Biol. 26, 5933–5945 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yamauchi, M. et al. Thyroid hormone activates adenosine 5′-monophosphate-activated protein kinase via intracellular calcium mobilization and activation of calcium/calmodulin-dependent protein kinase kinase-β. Mol. Endocrinol. 22, 893–903 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sinha, R. A. et al. Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling. Autophagy 11, 1341–1357 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ghislat, G., Patron, M., Rizzuto, R. & Knecht, E. Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-β (CaMKK-β). J. Biol. Chem. 287, 38625–38636 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mungai, P. T. et al. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol. Cell. Biol. 31, 3531–3545 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sallé-Lefort, S. et al. Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1α axis. Int. J. Oncol. 49, 1731–1736 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Sundararaman, A., Amirtham, U. & Rangarajan, A. Calcium-oxidant signaling network regulates AMP-activated protein kinase (AMPK) activation upon matrix deprivation. J. Biol. Chem. 291, 14410–14429 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Fogarty, S. et al. Calmodulin-dependent protein kinase kinase-β activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem. J. 426, 109–118 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Xiao, B. et al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 4, 3017 (2013).

    Article  PubMed  CAS  Google Scholar 

  83. Cokorinos, E. C. et al. Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice. Cell Metab. 25, 1147–1159.e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Myers, R. W. et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science 357, 507–511 (2017). This study, together with reference 83, demonstrates that small-molecule AMPK activators can restore insulin sensitivity and reduce glucose levels in diabetic rodent models and in primate models. The elegant use of liver-specific AMPK double knockout mice and skeletal muscle-specific AMPK double knockout mice demonstrates that only skeletal muscle AMPK is required for the glucose-lowering and insulin-sensitizing effects of these AMPK activators.

    Article  CAS  PubMed  Google Scholar 

  85. Smith, B. K. et al. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am. J. Physiol. Endocrinol. Metab. 311, E730–E740 (2016).

    Article  PubMed  Google Scholar 

  86. Woods, A. et al. Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep. 18, 3043–3051 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bultot, L. et al. AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem. J. 443, 193–203 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Eguchi, S. et al. AMP-activated protein kinase phosphorylates glutamine: fructose-6-phosphate amidotransferase 1 at Ser243 to modulate its enzymatic activity. Genes Cells 14, 179–189 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Zibrova, D. et al. GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. Biochem. J. 474, 983–1001 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Kawaguchi, T., Osatomi, K., Yamashita, H., Kabashima, T. & Uyeda, K. Mechanism for fatty acid 'sparing' effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J. Biol. Chem. 277, 3829–3835 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Hong, Y. H., Varanasi, U. S., Yang, W. & Leff, T. AMP-activated protein kinase regulates HNF4α transcriptional activity by inhibiting dimer formation and decreasing protein stability. J. Biol. Chem. 278, 27495–27501 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Leprivier, G. et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153, 1064–1079 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Faller, W. J. et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517, 497–500 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Li, Y.-H. et al. AMP-activated protein kinase directly phosphorylates and destabilizes Hedgehog pathway transcription factor GLI1 in medulloblastoma. Cell Rep. 12, 599–609 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mo, J.-S. et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17, 500–510 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. DeRan, M. et al. Energy stress regulates Hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep. 9, 495–503 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wang, W. et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17, 490–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rutherford, C. et al. Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Sci. Signal. 9, ra109 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. He, G. et al. AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol. Cell. Biol. 34, 148–157 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Chavez, J. A., Roach, W. G., Keller, S. R., Lane, W. S. & Lienhard, G. E. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J. Biol. Chem. 283, 9187–9195 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim, J. H. et al. Phospholipase D1 mediates AMP-activated protein kinase signaling for glucose uptake. PLoS ONE 5, e9600 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. McGarry, J. D., Leatherman, G. F. & Foster, D. W. Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. J. Biol. Chem. 253, 4128–4136 (1978).

    Article  CAS  PubMed  Google Scholar 

  104. Saggerson, D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu. Rev. Nutr. 28, 253–272 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Fullerton, M. D. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649–1654 (2013). This tour-de-force study using compound knock-in mice demonstrates that AMPK phosphorylation of ACC1 and ACC2 suppresses lipid accumulation in mice under normal dietary conditions and that AMPK-dependent suppression of ACC1 and ACC2 is required for metformin to reduce blood glucose levels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Quiros, P. M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Paul, M. H. & Sperling, E. Cyclophorase system. XXIII. Correlation of cyclophorase activity and mitochondrial density in striated muscle. Proc. Soc. Exp. Biol. Med. 79, 352–354 (1952).

    Article  CAS  PubMed  Google Scholar 

  108. Jornayvaz, F. R. & Shulman, G. I. Regulation of mitochondrial biogenesis. Essays Biochem. 47, 69–84 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Bergeron, R. et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 281, E1340–E1346 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Narkar, V. A. et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 134, 405–415 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Garcia-Roves, P. M., Osler, M. E., Holmström, M. H. & Zierath, J. R. Gain-of-function R225Q mutation in AMP-activated protein kinase γ3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 283, 35724–35734 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. O'Neill, H. M. et al. AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl Acad. Sci. USA 108, 16092–16097 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tanner, C. B. et al. Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1. Am. J. Physiol. Endocrinol. Metab. 305, E1018–E1029 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jeppesen, J. et al. LKB1 regulates lipid oxidation during exercise independently of AMPK. Diabetes 62, 1490–1499 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lantier, L. et al. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J. 28, 3211–3224 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. Mottillo, E. P. et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 24, 118–129 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Galic, S. et al. Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J. Clin. Invest. 121, 4903–4915 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hasenour, C. M. et al. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J. Biol. Chem. 289, 5950–5959 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Eichner, L. J. & Giguère, V. Estrogen related receptors (ERRs): a new dawn in transcriptional control of mitochondrial gene networks. Mitochondrion 11, 544–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Teyssier, C., Ma, H., Emter, R., Kralli, A. & Stallcup, M. R. Activation of nuclear receptor coactivator PGC-1α by arginine methylation. Genes Dev. 19, 1466–1473 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Li, X., Monks, B., Ge, Q. & Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator. Nature 447, 1012–1016 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Puigserver, P. et al. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARγ coactivator-1. Mol. Cell 8, 971–982 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Wu, Y. et al. Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo. Nat. Med. 21, 373–382 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Czubryt, M. P., McAnally, J., Fishman, G. I. & Olson, E. N. Regulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and mitochondrial function by MEF2 and HDAC5. Proc. Natl Acad. Sci. USA 100, 1711–1716 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. O'Neill, H. M., Holloway, G. P. & Steinberg, G. R. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol. Cell. Endocrinol. 366, 135–151 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Fisher, K. W. et al. AMPK promotes aberrant PGC1β expression to support human colon tumor cell survival. Mol. Cell. Biol. 35, 3866–3879 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wada, S. et al. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev. 30, 2551–2564 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ljubicic, V. & Jasmin, B. J. AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy. Trends Mol. Med. 19, 614–624 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Peralta, S. et al. Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration. Hum. Mol. Genet. 25, 3178–3191 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Marcinko, K. et al. The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice. Mol. Metab. 4, 643–651 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mounier, R., Théret, M., Lantier, L., Foretz, M. & Viollet, B. Expanding roles for AMPK in skeletal muscle plasticity. Trends Endocrinol. Metab. 26, 275–286 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Bujak, A. L. et al. AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metab. 21, 883–890 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mishra, P. & Chan, D. C. Metabolic regulation of mitochondrial dynamics. J. Cell Biol. 212, 379–387 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tondera, D. et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 28, 1589–1600 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589–598 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Rambold, A. S., Kostelecky, B., Elia, N. & Lippincott-Schwartz, J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc. Natl Acad. Sci. USA 108, 10190–10195 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32, 678–692 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Shirihai, O. S., Song, M. & Dorn, G. W. How mitochondrial dynamism orchestrates mitophagy. Circ. Res. 116, 1835–1849 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chan, D. C. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265–287 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Wai, T. & Langer, T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 27, 105–117 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Mishra, P., Carelli, V., Manfredi, G. & Chan, D. C. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 19, 630–641 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Otera, H. et al. Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J. Cell Biol. 191, 1141–1158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Losón, O. C., Song, Z., Chen, H. & Chan, D. C. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol. Biol. Cell 24, 659–667 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Smirnova, E., Griparic, L., Shurland, D. L. & van der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wang, C. & Youle, R. Cell biology: form follows function for mitochondria. Nature 530, 288–289 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. Abu-Elheiga, L. et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl Acad. Sci. USA 97, 1444–1449 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. O'Neill, H. M. et al. AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia 57, 1693–1702 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. O'Neill, H. M. et al. Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. Physiol. Rep. 3, e12444 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Cunniff, B., McKenzie, A. J., Heintz, N. H. & Howe, A. K. AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion. Mol. Biol. Cell 27, 2662–2674 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Bento, C. F. et al. Mammalian autophagy: how does it work? Annu. Rev. Biochem. 85, 685–713 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Chan, E. Y. W., Kir, S. & Tooze, S. A. siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J. Biol. Chem. 282, 25464–25474 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Russell, R. C., Yuan, H.-X. & Guan, K.-L. Autophagy regulation by nutrient signaling. Cell Res. 24, 42–57 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Park, J.-M. et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547–564 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Puente, C., Hendrickson, R. C. & Jiang, X. Nutrient-regulated phosphorylation of ATG13 inhibits starvation-induced autophagy. J. Biol. Chem. 291, 6026–6035 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Egan, D. F. et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol. Cell 59, 285–297 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Joo, J. H. et al. Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol. Cell 43, 572–585 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhou, C. et al. Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy. Cell Res. 27, 184–201 (2017).

    Article  CAS  PubMed  Google Scholar 

  164. Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741–750 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Joo, J. H. et al. The noncanonical role of ULK/ATG1 in ER-to-Golgi trafficking is essential for cellular homeostasis. Mol. Cell 62, 491–506 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wang, B. & Kundu, M. Canonical and noncanonical functions of ULK/Atg1. Curr. Opin. Cell Biol. 45, 47–54 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Wang, Z., Wilson, W. A., Fujino, M. A. & Roach, P. J. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol. Cell. Biol. 21, 5742–5752 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Meley, D. et al. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 281, 34870–34879 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Høyer-Hansen, M. et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol. Cell 25, 193–205 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Kim, J., Kundu, M., Viollet, B. & Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Itakura, E., Kishi-Itakura, C., Koyama-Honda, I. & Mizushima, N. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J. Cell Sci. 125, 1488–1499 (2012).

    CAS  PubMed  Google Scholar 

  172. Zhu, Y. et al. ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein Cell 4, 711–721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Honda, S. et al. Ulk1-mediated Atg5-independent macroautophagy mediates elimination of mitochondria from embryonic reticulocytes. Nat. Commun. 5, 4004 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Wu, W. et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 15, 566–575 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Zhu, H. et al. PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation. Autophagy 10, 1522–1534 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Li, J. et al. Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy. Autophagy 11, 1216–1229 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Yang, C.-S. et al. The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy. Autophagy 10, 785–802 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Inokuchi-Shimizu, S. et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J. Clin. Invest. 124, 3566–3578 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Weerasekara, V. K. et al. Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9. Mol. Cell. Biol. 34, 4379–4388 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290–303 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhang, D. et al. AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy 12, 1447–1459 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhao, Y. et al. RACK1 promotes autophagy by enhancing the Atg14L-Beclin 1-Vps34-Vps15 complex formation upon phosphorylation by AMPK. Cell Rep. 13, 1407–1417 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Xu, D.-Q. et al. PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity. EMBO J. 35, 496–514 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Nguyen, T. N., Padman, B. S. & Lazarou, M. Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol. 26, 733–744 (2016).

    Article  CAS  PubMed  Google Scholar 

  186. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  188. Kane, L. A. et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143–153 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Tian, W. et al. Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy. FEBS Lett. 589, 1847–1854 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. Miyamoto, T. et al. Compartmentalized AMPK signaling illuminated by genetically encoded molecular sensors and actuators. Cell Rep. 11, 657–670 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Pryde, K. R., Smith, H. L., Chau, K.-Y. & Schapira, A. H. V. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J. Cell Biol. 2213, 163–171 (2016).

    Article  CAS  Google Scholar 

  193. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat. Rev. Immunol. 7, 767–777 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Xie, N. et al. PRKAA/AMPK restricts HBV replication through promotion of autophagic degradation. Autophagy 12, 1507–1520 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Lv, S., Xu, Q.-Y., Sun, E.-C., Zhang, J.-K. & Wu, D.-L. Dissection and integration of the autophagy signaling network initiated by bluetongue virus infection: crucial candidates ERK1/2, Akt and AMPK. Sci. Rep. 6, 23130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Fan, X.-Y. et al. Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection. Sci. Rep. 5, 14728 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Brunton, J., Steele, S., Ziehr, B., Moorman, N. & Kawula, T. Feeding uninvited guests: mTOR and AMPK set the table for intracellular pathogens. PLoS Pathog. 9, e1003552 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472–483 (2007).

    Article  CAS  PubMed  Google Scholar 

  199. Bowman, C. J., Ayer, D. E. & Dynlacht, B. D. Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat. Cell Biol. 16, 1202–1214 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  201. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Li, X. et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol. Cell 66, 684–697.e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Mews, P. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 17, 1217–1386 (2017).

    Google Scholar 

  206. Friis, R. M. N. et al. Rewiring AMPK and mitochondrial retrograde signaling for metabolic control of aging and histone acetylation in respiratory-defective cells. Cell Rep. 7, 565–574 (2014).

    Article  CAS  PubMed  Google Scholar 

  207. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18, 3004–3009 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Curtis, R., O'Connor, G. & DiStefano, P. S. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5, 119–126 (2006).

    Article  CAS  PubMed  Google Scholar 

  209. Moreno-Arriola, E., El Hafidi, M., Ortega- Cuéllar, D. & Carvajal, K. AMP-activated protein kinase regulates oxidative metabolism in Caenorhabditis elegans through the NHR-49 and MDT-15 transcriptional regulators. PLoS ONE 11, e0148089 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Mandal, S., Guptan, P., Owusu-Ansah, E. & Banerjee, U. Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev. Cell 9, 843–854 (2005).

    Article  CAS  PubMed  Google Scholar 

  211. Moore, A. S. & Holzbaur, E. L. F. Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc. Natl Acad. Sci. USA 113, E3349–E3358 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Richter, B. et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc. Natl Acad. Sci. USA 113, 4039–4044 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Heo, J.-M., Ordureau, A., Paulo, J. A., Rinehart, J. & Harper, J. W. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60, 7–20 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Luchsinger, L. L., de Almeida, M. J., Corrigan, D. J., Mumau, M. & Snoeck, H.-W. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529, 528–531 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Forni, M. F., Peloggia, J., Trudeau, K., Shirihai, O. & Kowaltowski, A. J. Murine mesenchymal stem cell commitment to differentiation is regulated by mitochondrial dynamics. Stem Cells 34, 743–755 (2016).

    Article  CAS  PubMed  Google Scholar 

  217. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. An, H. & He, L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol. 228, R97–R106 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Coughlan, K. A., Valentine, R. J., Ruderman, N. B. & Saha, A. K. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab. Syndr. Obes. 7, 241–253 (2014).

    PubMed  PubMed Central  Google Scholar 

  221. Burkewitz, K., Weir, H. J. M. & Mair, W. B. AMPK as a pro-longevity target. EXS 107, 227–256 (2016).

    CAS  PubMed  Google Scholar 

  222. Burkewitz, K., Zhang, Y. & Mair, W. B. AMPK at the nexus of energetics and aging. Cell Metab. 20, 10–25 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Howell, J. J. et al. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 25, 463–471 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Quinn, B. J., Kitagawa, H., Memmott, R. M., Gills, J. J. & Dennis, P. A. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol. Metab. 24, 469–480 (2013).

    Article  CAS  PubMed  Google Scholar 

  227. Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Shackelford, D. B. et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Vila, I. K. et al. A UBE2O-AMPKα2 axis that promotes tumor initiation and progression offers opportunities for therapy. Cancer Cell 31, 208–224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Pineda, C. T. et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715–728 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Faubert, B. et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113–124 (2013).

    Article  CAS  PubMed  Google Scholar 

  232. Zadra, G. et al. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol. Med. 6, 519–538 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Lee, K.-H. et al. Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J. Biol. Chem. 286, 39247–39258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Huang, X. et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem. J. 412, 211–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  235. Saito, Y., Chapple, R. H., Lin, A., Kitano, A. & Nakada, D. AMPK protects leukemia-initiating cells in myeloid leukemias from metabolic stress in the bone marrow. Cell Stem Cell 17, 585–596 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Jeon, S.-M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Chan, L. N. et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479–483 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Kishton, R. J. et al. AMPK is essential to balance glycolysis and mitochondrial metabolism to control T-ALL cell stress and survival. Cell Metab. 23, 649–662 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).

    Article  CAS  PubMed  Google Scholar 

  240. Mizushima, N. et al. A protein conjugation system essential for autophagy. Nature 395, 395–398 (1998).

    Article  CAS  PubMed  Google Scholar 

  241. Ohsumi, Y. Historical landmarks of autophagy research. Cell Res. 24, 9–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  242. Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Birgisdottir, Å. B., Lamark, T. & Johansen, T. The LIR motif — crucial for selective autophagy. J. Cell Sci. 126, 3237–3247 (2013).

    Article  CAS  PubMed  Google Scholar 

  244. Laker, R. C. et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat. Commun. 8, 548 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

S.H. is supported by an Advanced PostDoc.Mobility fellowship of the Swiss National Science Foundation. R.J.S. holds the William R. Brody Chair. The work from the authors' laboratory described in this Review was supported by grants from the US National Institutes of Health (R01DK080425, R01CA172229, P01CA120964) and The Leona M. and Harry B. Helmsley Charitable Trust (grant #2012-PGMED002).

Author information

Authors and Affiliations

Authors

Contributions

S.H. and R.J.S. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Reuben J. Shaw.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Allosteric mechanism

Modulation of protein activity by the binding of a molecule to a specific site, often associated with a change in conformation.

Axin

A protein involved in WNT pathway signalling regulation and in mTOR signalling at the lysosome.

Acetyl-CoA carboxylases

Enzymes that catalyse the first step in de novo lipid synthesis, the carboxylation of acetyl-CoA to malonyl-CoA.

Metformin

A widely prescribed type 2 diabetes drug. Mechanistically, metformin inhibits complex I of the respiratory chain and leads to changes in the ATP-to-AMP ratio and activation of AMP-activated protein kinase (AMPK).

Mitophagy

Specific removal of mitochondria by autophagy.

Complex I and complex III

Complexes of the respiratory chain in the mitochondrial inner membrane that couple the transfer of electrons to proton pumping. The proton gradient created by the respiratory chain is used to produce ATP, while the electrons are transferred to molecular oxygen.

Dynamin-like protein DRP1

A protein necessary for mitochondrial fission. DRP1 is recruited to mitochondria at sites of future division and mediates the constriction of mitochondria.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Herzig, S., Shaw, R. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19, 121–135 (2018). https://doi.org/10.1038/nrm.2017.95

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2017.95

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing