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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 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).

    CAS  Google Scholar 

  2. 2

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

    CAS  Google Scholar 

  3. 3

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

    PubMed  PubMed Central  Google Scholar 

  4. 4

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

    CAS  Google Scholar 

  5. 5

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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).

    CAS  Google Scholar 

  7. 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).

    CAS  Google Scholar 

  8. 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).

    CAS  Google Scholar 

  9. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    CAS  Google Scholar 

  11. 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).

    CAS  Google Scholar 

  12. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    CAS  Google Scholar 

  15. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    CAS  Google Scholar 

  17. 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).

    Google Scholar 

  18. 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).

    CAS  Google Scholar 

  19. 19

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

    CAS  Google Scholar 

  20. 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).

    CAS  Google Scholar 

  21. 21

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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

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

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

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

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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.

    CAS  Google Scholar 

  31. 31

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

    CAS  Google Scholar 

  32. 32

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

    CAS  Google Scholar 

  33. 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).

    CAS  Google Scholar 

  34. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    CAS  Google Scholar 

  37. 37

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

    CAS  Google Scholar 

  38. 38

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

    CAS  Google Scholar 

  39. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    CAS  Google Scholar 

  42. 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).

    PubMed  PubMed Central  Google Scholar 

  43. 43

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

    CAS  Google Scholar 

  44. 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).

    CAS  Google Scholar 

  45. 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).

    CAS  Google Scholar 

  46. 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).

    CAS  Google Scholar 

  47. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

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

    CAS  Google Scholar 

  51. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

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

    CAS  Google Scholar 

  54. 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).

    CAS  Google Scholar 

  55. 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).

    CAS  Google Scholar 

  56. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 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).

    CAS  Google Scholar 

  58. 58

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

    CAS  Google Scholar 

  59. 59

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

    CAS  Google Scholar 

  60. 60

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

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

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

    CAS  Google Scholar 

  64. 64

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

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  Google Scholar 

  67. 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).

    CAS  Google Scholar 

  68. 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).

    CAS  Google Scholar 

  69. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

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

    CAS  Google Scholar 

  71. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 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).

    PubMed  PubMed Central  Google Scholar 

  73. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

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

    Google Scholar 

  79. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    CAS  Google Scholar 

  82. 82

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

    PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  Google Scholar 

  84. 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.

    CAS  Google Scholar 

  85. 85

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

    Google Scholar 

  86. 86

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

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

    CAS  Google Scholar 

  88. 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).

    CAS  Google Scholar 

  89. 89

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

    CAS  Google Scholar 

  90. 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).

    CAS  Google Scholar 

  91. 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).

    CAS  Google Scholar 

  92. 92

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

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

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

    CAS  Google Scholar 

  94. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

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

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    Google Scholar 

  99. 99

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

    CAS  Google Scholar 

  100. 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).

    PubMed  PubMed Central  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

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

    PubMed  PubMed Central  Google Scholar 

  103. 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).

    CAS  Google Scholar 

  104. 104

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

    CAS  Google Scholar 

  105. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

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

    CAS  Google Scholar 

  107. 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).

    CAS  Google Scholar 

  108. 108

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

    CAS  Google Scholar 

  109. 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).

    CAS  Google Scholar 

  110. 110

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

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 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).

    CAS  Google Scholar 

  112. 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).

    CAS  Google Scholar 

  113. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

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

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

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

    CAS  Google Scholar 

  116. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

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

    CAS  Google Scholar 

  120. 120

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

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    CAS  Google Scholar 

  122. 122

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

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

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

    CAS  Google Scholar 

  124. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  Google Scholar 

  126. 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).

    CAS  Google Scholar 

  127. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 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).

    CAS  Google Scholar 

  129. 129

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

    PubMed  PubMed Central  Google Scholar 

  130. 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).

    CAS  Google Scholar 

  131. 131

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

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 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).

    CAS  Google Scholar 

  135. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 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).

    CAS  Google Scholar 

  138. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

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

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

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

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 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).

    CAS  Google Scholar 

  143. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

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

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

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

    CAS  Google Scholar 

  146. 146

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

    CAS  Google Scholar 

  147. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 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).

    PubMed  PubMed Central  Google Scholar 

  150. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

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

    CAS  Google Scholar 

  152. 152

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

    CAS  Google Scholar 

  153. 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).

    CAS  Google Scholar 

  154. 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).

    PubMed  PubMed Central  Google Scholar 

  155. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

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

    CAS  Google Scholar 

  157. 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).

    CAS  Google Scholar 

  158. 158

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

    CAS  Google Scholar 

  159. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

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

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

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

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 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).

    CAS  Google Scholar 

  164. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

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

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

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

    CAS  Google Scholar 

  169. 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).

    Google Scholar 

  170. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 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  Google Scholar 

  172. 172

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

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

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

    CAS  Google Scholar 

  174. 174

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

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

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

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

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

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

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

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

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

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 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).

    PubMed  PubMed Central  Google Scholar 

  181. 181

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

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

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

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 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).

    CAS  Google Scholar 

  184. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

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

    CAS  Google Scholar 

  186. 186

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

    PubMed  PubMed Central  Google Scholar 

  187. 187

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

    CAS  Google Scholar 

  188. 188

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

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

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

    CAS  Google Scholar 

  190. 190

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

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

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

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 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).

    Google Scholar 

  193. 193

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

    CAS  Google Scholar 

  194. 194

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

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 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).

    PubMed  PubMed Central  Google Scholar 

  198. 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).

    CAS  Google Scholar 

  199. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

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

    CAS  Google Scholar 

  201. 201

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

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

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

    PubMed  PubMed Central  Google Scholar 

  204. 204

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

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

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

    Google Scholar 

  206. 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).

    CAS  Google Scholar 

  207. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 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).

    CAS  Google Scholar 

  209. 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).

    PubMed  PubMed Central  Google Scholar 

  210. 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).

    CAS  Google Scholar 

  211. 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  Google Scholar 

  212. 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).

    CAS  Google Scholar 

  213. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215

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

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 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).

    CAS  Google Scholar 

  217. 217

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

    PubMed  PubMed Central  Google Scholar 

  218. 218

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

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219

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

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 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. 221

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

    CAS  Google Scholar 

  222. 222

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

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223

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

    CAS  PubMed  PubMed Central  Google Scholar 

  224. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 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).

    CAS  Google Scholar 

  227. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

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

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 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).

    CAS  Google Scholar 

  232. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 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).

    CAS  Google Scholar 

  235. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237

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

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. 239

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

    CAS  Google Scholar 

  240. 240

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

    CAS  Google Scholar 

  241. 241

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

    CAS  Google Scholar 

  242. 242

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

    CAS  PubMed  PubMed Central  Google Scholar 

  243. 243

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

    CAS  Google Scholar 

  244. 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).

    PubMed  PubMed Central  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

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

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

Further reading

Search

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