AMPK: Guardian of metabolism and mitochondrial homeostasis

Nature Reviews Molecular Cell Biology

Volumn 19, Issue 2, 2018, Pages 121-135

  Herzig, Sébastien ^a   Shaw, Reuben J ^a  

^a SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; PHOSPHOTRANSFERASE; ADENOSINE TRIPHOSPHATASE; PROTEIN SERINE THREONINE KINASE;

AUTOPHAGY; BIOSYNTHESIS; CATABOLISM; CELLULAR DISTRIBUTION; ENZYME ACTIVATION; ENZYME LOCALIZATION; ENZYME STRUCTURE; LYSOSOME; METABOLIC REGULATION; METABOLISM; MITOCHONDRIAL BIOGENESIS; MITOCHONDRIAL DYNAMICS; MITOCHONDRION; MITOPHAGY; NONHUMAN; PRIORITY JOURNAL; PROTEIN QUATERNARY STRUCTURE; REVIEW; STRESS; TRANSCRIPTION REGULATION; ANIMAL; ENERGY METABOLISM; HOMEOSTASIS; HUMAN; PHOSPHORYLATION; PHYSIOLOGY;

ADENOSINE TRIPHOSPHATASES; AMP-ACTIVATED PROTEIN KINASES; ANIMALS; AUTOPHAGY; ENERGY METABOLISM; HOMEOSTASIS; HUMANS; MITOCHONDRIA; PHOSPHORYLATION; PROTEIN-SERINE-THREONINE KINASES;

EID: 85041140494     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm.2017.95     Document Type: Review

References (244)

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).
2. Gancedo, J. M. Carbon catabolite repression in yeast. Eur. J. Biochem. 206, 297-313 (1992).
3. Crozet, P. et al. Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases. Front. Plant Sci. 5, 190 (2014).
4. Inoki, K., Zhu, T. & Guan, K.-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590 (2003).
5. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214-226 (2008).
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).
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).
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).
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).
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).
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).
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).
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).
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).
15. Toyama, E. Q. et al. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275-281 (2016).
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).
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).
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).
19. Koo, S.-H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109-1111 (2005).
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).
21. Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437-440 (2009).
22. Bungard, D. et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201-1205 (2010).
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).
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).
25. Shin, H.-J. R. et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534, 553-557 (2016).
26. Young, N. P. et al. AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes. Genes Dev. 30, 535-552 (2016).
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).
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).
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).
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).
31. Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45, 31-37 (2017).
32. Stapleton, D. et al. Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem. 271, 611-614 (1996).
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).
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).
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).
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).
37. Xiao, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496-500 (2007).
38. Hardie, D. G., Carling, D. & Gamblin, S. J. AMP-activated protein kinase: also regulated by ADP? Trends Biochem. Sci. 36, 470-477 (2011).
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).
40. Ross, F. A., Jensen, T. E. & Hardie, D. G. Differential regulation by AMP and ADP of AMPK complexes containing different y subunit isoforms. Biochem. J. 473, 189-199 (2016).
41. 2+/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J. Biol. Chem. 270, 27186-27191 (1995).
42. Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRAD oc/p and MO25 ot/p are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).
43. Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004-2008 (2003).
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).
45. Oakhill, J. S. et al. p-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).
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-2Ca and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421-425 (1995).
47. Birk, J. B. & Wojtaszewski, J. F. P. Predominant a2/p2/y3 AMPK activation during exercise in human skeletal muscle. J. Physiol. 577, 1021-1032 (2006).
48. Jensen, T. E. et al. PT-1 selectively activates AMPK-y1 complexes in mouse skeletal muscle, but activates all three ysubunit complexes in cultured human cells by inhibiting the respiratory chain. Biochem. J. 467, 461-472 (2015).
49. Rajamohan, F. et al. Probing the enzyme kinetics, allosteric modulation and activation of a 1-and cc2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem. J. 473, 581-592 (2016).
50. 2 in human skeletal muscle. Diabetes 52, 926-928 (2003).
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 a2 form of AMP-activated protein kinase. Mol. Cell. Biol. 27, 4317-4327 (2007).
52. Pinter, K., Grignani, R. T., Watkins, H. & Redwood, C. Localisation of AMPK y subunits in cardiac and skeletal muscles. J. Muscle Res. Cell Motil. 34, 369-378 (2013).
53. Liang, J. et al. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat. Commun. 6, 7926 (2015).
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).
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).
56. Zhang, C.-S. et al. Fructose-1, 6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548, 112-116 (2017).
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).
58. Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443-452 (2006).
59. Alessi, D. R., Sakamoto, K. & Bayascas, J. R. LKB1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137-163 (2006).
60. Ikeda, Y. et al. Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J. Biol. Chem. 284, 35839-35849 (2009).
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).
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).
63. Ollila, S. & Mäkelä, T P. The tumor suppressor kinase LKB1: lessons from mouse models. J. Mol. Cell. Biol. 3, 330-340 (2011).
64. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642-1646 (2005).
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).
66. 2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060-29066 (2005).
67. Hawley, S. A. et al. Calmodulin-dependent protein kinase kinase-p is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9-19 (2005).
68. 2+/calmodulin-dependent protein kinase kinase-p acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21-33 (2005).
69. 2+/calmodulin/CaMKK2 axis: nature's metabolic CaMshaft Trends Endocrinol. Metab. 27, 706-718 (2016).
70. Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377-388 (2008).
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).
72. 2+ in T lymphocytes. J. Exp. Med. 203, 1665-1670 (2006).
73. 2+/calmodulin-dependent protein kinase kinase β. Mol. Cell. Biol. 26, 5933-5945 (2006).
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).
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).
76. 2+/calmodulin-dependent kinase kinase-β (CaMKK-β). J. Biol. Chem. 287, 38625-38636 (2012).
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).
78. Sallé-Lefort, S. et al. Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1α axis. Int. J. Oncol. 49, 1731-1736 (2016).
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).
80. 2+ and AMP. Biochem. J. 426, 109-118 (2010).
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).
82. Xiao, B. et al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 4, 3017 (2013).
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).
84. Myers, R. W. et al. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science 357, 507-511 (2017).
85. Smith, B. K. et al. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am. J. Physiol. Endocrinol. Metab. 311, E730-E740 (2016).
86. Woods, A. et al. Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep. 18, 3043-3051 (2017).
87. Bultot, L. et al. AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem. J. 443, 193-203 (2012).
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).
89. Zibrova, D. et al. GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis. Biochem. J. 474, 983-1001 (2017).
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).
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).
92. Leprivier, G. et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153, 1064-1079 (2013).
93. Faller, W. J. et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517, 497-500 (2015).
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).
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).
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).
97. Wang, W. et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat. Cell Biol. 17, 490-499 (2015).
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).
99. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283-293 (2005).
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).
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).
102. Kim, J. H. et al. Phospholipase D1 mediates AMP-activated protein kinase signaling for glucose uptake. PLoS ONE 5, e9600 (2010).
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).
104. Saggerson, D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu. Rev. Nutr. 28, 253-272 (2008).
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).
106. Quiros, P. M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213-226 (2016).
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).
108. Jornayvaz, F. R. & Shulman, G. I. Regulation of mitochondrial biogenesis. Essays Biochem. 47, 69-84 (2010).
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).
110. Narkar, V. A. et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 134, 405-415 (2008).
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).
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).
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).
114. Jeppesen, J. et al. LKB1 regulates lipid oxidation during exercise independently of AMPK. Diabetes 62, 1490-1499 (2013).
115. Lantier, L. et al. AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. FASEB J. 28, 3211-3224 (2014).
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).
117. Galic, S. et al. Hematopoietic AMPK p1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J. Clin. Invest. 121, 4903-4915 (2011).
118. Hasenour, C. M. et al. 5-Aminoimidazole-4-carboxamide-1-p-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).
119. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829-839 (1998).
120. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115-124 (1999).
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).
122. Lin, J. et al. Transcriptional co-activator PGC-1 a drives the formation of slow-twitch muscle fibres. Nature 418, 797-801 (2002).
123. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1 a and SIRT1. Nature 434, 113-118 (2005).
124. Teyssier, C, Ma, H., Emter, R., Kralli, A. & Stallcup, M. R. Activation of nuclear receptor coactivator PGC-1 a by arginine methylation. Genes Dev 19, 1466-1473 (2005).
125. Li, X., Monks, B., Ge, Q. & Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1 a transcription coactivator. Nature 447, 1012-1016 (2007).
126. Puigserver, P. et al. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARycoactivator-1. Mol. Cell 8, 971-982 (2001).
127. Wu, Y. et al. Activation of AMPKa2 in adipocytes is essential for nicotine-induced insulin resistance in vivo. Nat. Med. 21, 373-382 (2015).
128. Czubryt, M. P., McAnally, J., Fishman, G. I. & Olson, E. N. Regulation of peroxisome proliferator-activated receptor y coactivator 1 a (PGC-1 a) and mitochondrial function by MEF2 and HDAC5. Proc. Natl Acad. Sci. USA 100, 1711-1716 (2003).
129. Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-1060 (2009).
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).
131. Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647-658 (2013).
132. Fisher, K. W. et al. AMPK promotes aberrant PGC1 p expression to support human colon tumor cell survival. Mol. Cell. Biol. 35, 3866-3879 (2015).
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).
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).
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).
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).
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).
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).
139. Mishra, P. & Chan, D. C. Metabolic regulation of mitochondrial dynamics. J. Cell Biol. 212, 379-387 (2016).
140. Tondera, D. et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 28, 1589-1600 (2009).
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).
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).
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).
144. Shirihai, O. S., Song, M. & Dorn, G. W. How mitochondrial dynamism orchestrates mitophagy. Circ. Res. 116, 1835-1849 (2015).
145. Chan, D. C. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265-287 (2012).
146. Wai, T. & Langer, T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol. Metab. 27, 105-117 (2016).
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).
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).
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).
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).
151. Wang, C. & Youle, R. Cell biology: form follows function for mitochondria. Nature 530, 288-289 (2016).
152. Abu-Elheiga, L. et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl Acad. Sci. USA 97, 1444-1449 (2000).
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).
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).
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).
156. Bento, C. F. et al. Mammalian autophagy: how does it work? Annu. Rev. Biochem. 85, 685-713 (2016).
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).
158. Russell, R. C., Yuan, H.-X. & Guan, K.-L. Autophagy regulation by nutrient signaling. Cell Res. 24, 42-57 (2014).
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).
160. Puente, C., Hendrickson, R. C. & Jiang, X. Nutrient-regulated phosphorylation of ATG13 inhibits starvation-induced autophagy. J. Biol. Chem. 291, 6026-6035 (2016).
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).
162. Joo, J. H. et al. Hsp90-Cdc37 chaperone complex regulates Ulk1-and Atg13-mediated mitophagy. Mol. Cell 43, 572-585 (2011).
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).
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).
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).
166. Wang, B. & Kundu, M. Canonical and noncanonical functions of ULK/Atg1. Curr. Opin. Cell Biol. 45, 47-54 (2017).
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).
168. Meley, D. et al. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 281, 34870-34879 (2006).
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).
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).
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).
172. Zhu, Y. et al. ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein Cell 4, 711-721 (2013).
173. Honda, S. et al. Ulk1-mediated Atg5-independent macroautophagy mediates elimination of mitochondria from embryonic reticulocytes. Nat. Commun. 5, 4004 (2014).
174. Wu, W. et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 15, 566-575 (2014).
175. Zhu, H. et al. PRKAA1/AMPKα1 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation. Autophagy 10, 1522-1534 (2014).
176. Li, J. et al. Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy. Autophagy 11, 1216-1229 (2015).
177. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309-314 (2015).
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).
179. Inokuchi-Shimizu, S. et al. TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J. Clin. Invest. 124, 3566-3578 (2014).
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).
181. Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290-303 (2013).
182. Zhang, D. et al. AMPK regulates autophagy by phosphorylating BECN1 at threonine 388. Autophagy 12, 1447-1459 (2016).
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).
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).
185. Nguyen, T. N., Padman, B. S. & Lazarou, M. Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol. 26, 733-744 (2016).
186. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).
187. Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162-166 (2014).
188. Kane, L. A. et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143-153 (2014).
189. Tian, W. et al. Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy. FEBS Lett. 589, 1847-1854 (2015).
190. Miyamoto, T. et al. Compartmentalized AMPK signaling illuminated by genetically encoded molecular sensors and actuators. Cell Rep. 11, 657-670 (2015).
191. Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433-446 (2008).
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).
193. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat. Rev. Immunol. 7, 767-777 (2007).
194. Xie, N. et al. PRKAA/AMPK restricts HBV replication through promotion of autophagic degradation. Autophagy 12, 1507-1520 (2016).
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).
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).
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).
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).
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).
200. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473-477 (2009).
201. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433 (2011).
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).
203. Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).
204. Li, X. et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol. Cell 66, 684-697.e9 (2017).
205. Mews, P. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 17, 1217-1386 (2017).
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).
207. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulinlike signals to lifespan in C. elegans. Genes Dev. 18, 3004-3009 (2004).
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).
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).
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).
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).
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).
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).
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).
215. Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205-210 (2017).
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).
217. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553-557 (2015).
218. Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63-76 (2016).
219. An, H. & He, L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol. 228, R97-R106 (2016).
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).
221. Burkewitz, K., Weir, H. J. M. & Mair, W. B. AMPK as a pro-longevity target. EXS 107, 227-256 (2016).
222. Burkewitz, K., Zhang, Y. & Mair, W. B. AMPK at the nexus of energetics and aging. Cell Metab. 20, 10-25 (2014).
223. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167-1174 (2001).
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).
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).
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).
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).
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).
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).
230. Pineda, C. T. et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715-728 (2015).
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).
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).
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).
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).
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).
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).
237. Chan, L. N. et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479-483 (2017).
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).
239. Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169-174 (1993).
240. Mizushima, N. et al. A protein conjugation system essential for autophagy. Nature 395, 395-398 (1998).
241. Ohsumi, Y. Historical landmarks of autophagy research. Cell Res. 24, 9-23 (2014).
242. Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445-544 (2012).
243. Birgisdottir, Å. B., Lamark, T. & Johansen, T. The LIR motif-crucial for selective autophagy. J. Cell Sci. 126, 3237-3247 (2013).
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).