Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).
Lumeng, C. N. & Saltiel, A. R. Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121, 2111–2117 (2011).
O’Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).
Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion—from mechanism to translation. Nat. Med. 17, 1391–1401 (2011).
Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).
Beers, M. F. & Morrisey, E. E. The three R’s of lung health and disease: repair, remodeling, and regeneration. J. Clin. Invest. 121, 2065–2073 (2011).
Thannickal, V. J., Zhou, Y., Gaggar, A. & Duncan, S. R. Fibrosis: ultimate and proximate causes. J. Clin. Invest. 124, 4673–4677 (2014).
Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. 8, 241–276 (2013).
Bueno, M. et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin. Invest. 125, 521–538 (2015).
Kobayashi, K. et al. Involvement of PARK2-mediated mitophagy in idiopathic pulmonary fibrosis pathogenesis. J. Immunol. 197, 504–516 (2016).
Bernard, K. et al. Metabolic reprogramming is required for myofibroblast contractility and differentiation. J. Biol. Chem. 290, 25427–25438 (2015).
Ramos, C. et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am. J. Respir. Cell Mol. Biol. 24, 591–598 (2001).
Romero, Y. et al. mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 15, 1103–1112 (2016).
Ashley, S. L. et al. Targeting inhibitor of apoptosis proteins protects from bleomycin-induced lung fibrosis. Am. J. Respir. Cell Mol. Biol. 54, 482–492 (2016).
Hecker, L. et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci. Transl. Med. 6, 231ra247 (2014).
Inoki, K., Kim, J. & Guan, K. L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400 (2012).
Shaw, R. J. Metformin trims fats to restore insulin sensitivity. Nat. Med. 19, 1570–1572 (2013).
Riera, C. E. & Dillin, A. Can aging be ‘drugged’? Nat. Med. 21, 1400–1405 (2015).
Finkel, T. The metabolic regulation of aging. Nat. Med. 21, 1416–1423 (2015).
Burkewitz, K., Zhang, Y. & Mair, W. B. AMPK at the nexus of energetics and aging. Cell Metab. 20, 10–25 (2014).
Salminen, A. & Kaarniranta, K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res. Rev. 11, 230–241 (2012).
Park, C. S. et al. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem. Pharmacol. 84, 1660–1670 (2012).
Liu, Z. et al. AMP-activated protein kinase and glycogen synthase kinase 3β modulate the severity of sepsis-induced lung injury. Mol. Med. 21, 937–950 (2015).
Sato, N. et al. Metformin attenuates lung fibrosis development via NOX4 suppression. Respir. Res. 17, 107 (2016).
Mishra, R. et al. AMP-activated protein kinase inhibits transforming growth factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J. Biol. Chem. 283, 10461–10469 (2008).
Thakur, S. et al. Activation of AMP-activated protein kinase prevents TGF-β1-induced epithelial-mesenchymal transition and myofibroblast activation. Am. J. Pathol. 185, 2168–2180 (2015).
Lim, J. Y., Oh, M. A., Kim, W. H., Sohn, H. Y. & Park, S. I. AMP-activated protein kinase inhibits TGF-β-induced fibrogenic responses of hepatic stellate cells by targeting transcriptional coactivator p300. J. Cell Physiol. 227, 1081–1089 (2012).
Li, L. et al. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway. Oncotarget 6, 43605–43619 (2015).
Park, I. H. et al. Metformin reduces TGF-β1-induced extracellular matrix production in nasal polyp-derived fibroblasts. Otolaryngol. Head Neck Surg. 150, 148–153 (2014).
Kottmann, R. M. et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-beta. Am. J. Respir. Crit. Care Med. 186, 740–751 (2012).
Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
Parsons, M. J. & Green, D. R. Mitochondria in cell death. Essays Biochem. 47, 99–114 (2010).
Tait, S. W. & Green, D. R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621–632 (2010).
Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).
Spoden, G. A. et al. Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell size and apoptotic cell death dependent on glucose supply. Exp. Cell Res. 315, 2765–2774 (2009).
Horowitz, J. C. et al. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-β1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J. Biol. Chem. 279, 1359–1367 (2004).
Foretz, M., Guigas, B., Bertrand, L., Pollak, M. & Viollet, B. Metformin: from mechanisms of action to therapies. Cell Metab. 20, 953–966 (2014).
Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).
Yu, G. et al. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat. Med. 24, 39–49 (2018).
Jiang, S. et al. Mitochondria and AMP-activated protein kinase-dependent mechanism of efferocytosis. J. Biol. Chem. 288, 26013–26026 (2013).
Jian, M. Y., Alexeyev, M. F., Wolkowicz, P. E., Zmijewski, J. W. & Creighton, J. R. Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 305, L844–855 (2013).
Hecker, L. et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat. Med. 15, 1077–1081 (2009).
Jiang, S. et al. Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury. J. Immunol. 192, 4795–4803 (2014).
Franco-Barraza, J., Beacham, D. A., Amatangelo, M. D., & Cukierman, E. Preparation of extracellular matrices produced by cultured and primary fibroblasts. Curr. Protoc. Cell Biol. 71, 10.9.1–10.9.34 (2016).
Hill, B. G. et al. Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol. Chem. 393, 1485–1512 (2012).
Graham, L. & Orenstein, J.M. Processing tissue and cells for transmission electron microscopy in diagnostic pathology and research. Nat. Protoc. 2, 2439–2450 (2007).