1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Physiology
  4. Volume 81, 2019
  5. Article

Annual Review of Physiology

Volume 81, 2019

Cellular Metabolism in Lung Health and Disease

Abstract

The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain. For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation. However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant. While many extrapulmonary diseases are now linked to abnormalities in cellular metabolism, the pulmonary community has only recently embraced the concept of metabolic dysfunction as a driver of respiratory pathology. Herein, we provide an overview of the major metabolic pathways in the lung and discuss how cells sense and adapt to low-energy states. Moreover, we review some of the emerging evidence that links alterations in cellular metabolism to the pathobiology of several common respiratory diseases.

Keyword(s): cellular metabolism, energy, glycolysis, lung, mitochondria, respiratory disease
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-020518-114640
2019-02-10
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/physiol/81/1/annurev-physiol-020518-114640.html?itemId=/content/journals/10.1146/annurev-physiol-020518-114640&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS et al. 2001. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 128:5181–88
     [Google Scholar]
  2. 2.
    Summer R, Fitzsimmons K, Dwyer D, Murphy J, Fine A 2007. Isolation of an adult mouse lung mesenchymal progenitor cell population. Am. J. Respir. Cell Mol. Biol. 37:152–59
     [Google Scholar]
  3. 3.
    Summer R, Kotton DN, Sun X, Ma B, Fitzsimmons K, Fine A 2003. Side population cells and Bcrp1 expression in lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 285:L97–104
     [Google Scholar]
  4. 4.
    Romero F, Hong X, Shah D, Kallen CB, Rosas I et al. 2018. Lipid synthesis is required to resolve ER stress and limit fibrotic responses in the lung. Am. J. Respir. Cell Mol. Biol. 59: https://doi.org/10.1165/rcmb.2017-0340OC
    [Crossref] [Google Scholar]
  5. 5.
    Cloonan SM, Glass K, Laucho-Contreras ME, Bhashyam AR, Cervo M et al. 2016. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat. Med. 22:163–74
     [Google Scholar]
  6. 6.
    Rhoades RA. 1974. Net uptake of glucose, glycerol, and fatty acids by the isolated perfused rat lung. Am. J. Physiol. 226:144–49
     [Google Scholar]
  7. 7.
    O'Neil JJ, Tierney DF 1974. Rat lung metabolism: glucose utilization by isolated perfused lungs and tissue slices. Am. J. Physiol. 226:867–73
     [Google Scholar]
  8. 8.
    Tierney DF. 1974. Intermediary metabolism of the lung. Fed. Proc. 33:2232–37
     [Google Scholar]
  9. 9.
    Vander Heiden MG, Cantley LC, Thompson CB 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–33
     [Google Scholar]
  10. 10.
    Warburg O, Wind F, Negelein E 1927. The metabolism of tumors in the body. J. Gen. Physiol. 8:519–30
     [Google Scholar]
  11. 11.
    Faubert B, Li KY, Cai L, Hensley CT, Kim J et al. 2017. Lactate metabolism in human lung tumors. Cell 171:358–71.e9
     [Google Scholar]
  12. 12.
    Zu XL, Guppy M 2004. Cancer metabolism: facts, fantasy, and fiction. Biochem. Biophys. Res. Commun. 313:459–65
     [Google Scholar]
  13. 13.
    Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E 2007. Energy metabolism in tumor cells. FEBS J 274:1393–418
     [Google Scholar]
  14. 14.
    Hume DA, Weidemann MJ 1979. Role and regulation of glucose metabolism in proliferating cells. J. Natl. Cancer Inst. 62:3–8
     [Google Scholar]
  15. 15.
    Fisher AB. 1984. Intermediary metabolism of the lung. Environ. Health Perspect. 55:149–58
     [Google Scholar]
  16. 16.
    Tierney DF. 1971. Lactate metabolism in rat lung tissue. Arch. Intern. Med. 127:858–60
     [Google Scholar]
  17. 17.
    Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR et al. 2013. Type 2 alveolar cells are stem cells in adult lung. J. Clin. Investig. 123:3025–36
     [Google Scholar]
  18. 18.
    Bowden DH. 1983. Cell turnover in the lung. Am. Rev. Respir. Dis. 128:S46–48
     [Google Scholar]
  19. 19.
    Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG et al. 2015. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517:621–25
     [Google Scholar]
  20. 20.
    Bassett DJ, Fisher AB 1976. Metabolic response to carbon monoxide by isolated rat lungs. Am. J. Physiol. 230:658–63
     [Google Scholar]
  21. 21.
    Fisher AB, Steinberg H, Bassett D 1974. Energy utilization by the lung. Am. J. Med. 57:437–46
     [Google Scholar]
  22. 22.
    Chettimada S, Gupte R, Rawat D, Gebb SA, McMurtry IF, Gupte SA 2015. Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 308:L287–300
     [Google Scholar]
  23. 23.
    Fisher AB, Itakura N, Dodia C, Thurman RG 1981. Pulmonary mixed-function oxidation: stimulation by glucose and the effects of metabolic inhibitors. Biochem. Pharmacol. 30:379–83
     [Google Scholar]
  24. 24.
    Bassett DJ, Fisher AB 1976. Pentose cycle activity of the isolated perfused rat lung. Am. J. Physiol. 231:1527–32
     [Google Scholar]
  25. 25.
    Tierney D, Ayers L, Herzog S, Yang J 1973. Pentose pathway and production of reduced nicotinamide adenine dinucleotide phosphate. A mechanism that may protect lungs from oxidants. Am. Rev. Respir. Dis. 108:1348–51
     [Google Scholar]
  26. 26.
    Carracedo A, Cantley LC, Pandolfi PP 2013. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13:227–32
     [Google Scholar]
  27. 27.
    Shaw ME, Rhoades RA 1977. Substrate metabolism in the perfused lung: response to changes in circulating glucose and palmitate levels. Lipids 12:930–35
     [Google Scholar]
  28. 28.
    Eaton S, Bartlett K, Pourfarzam M 1996. Mammalian mitochondrial beta-oxidation. Biochem. J. 320:Part 2345–57
     [Google Scholar]
  29. 29.
    Wanders RJ, Waterham HR 2006. Biochemistry of mammalian peroxisomes revisited. Annu. Rev. Biochem. 75:295–332
     [Google Scholar]
  30. 30.
    Abe M, Tierney DF 1977. Lung lipid metabolism after 7 days of hydrocortisone administration to adult rats. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 42:202–5
     [Google Scholar]
  31. 31.
    Bohlin K, Merchak A, Spence K, Patterson BW, Hamvas A 2003. Endogenous surfactant metabolism in newborn infants with and without respiratory failure. Pediatr. Res. 54:185–91
     [Google Scholar]
  32. 32.
    Harayama T, Eto M, Shindou H, Kita Y, Otsubo E et al. 2014. Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo. Cell Metab 20:295–305
     [Google Scholar]
  33. 33.
    Haagsman HP, van Golde LM 1991. Synthesis and assembly of lung surfactant. Annu. Rev. Physiol. 53:441–64
     [Google Scholar]
  34. 34.
    Goodpaster BH, Sparks LM 2017. Metabolic flexibility in health and disease. Cell Metab 25:1027–36
     [Google Scholar]
  35. 35.
    Köhler P. 1985. The strategies of energy conservation in helminths. Mol. Biochem. Parasitol. 17:1–18
     [Google Scholar]
  36. 36.
    Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV et al. 2011. Structure of mammalian AMPK and its regulation by ADP. Nature 472:230–33
     [Google Scholar]
  37. 37.
    Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J et al. 2005. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19
     [Google Scholar]
  38. 38.
    Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG et al. 2003. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13:2004–8
     [Google Scholar]
  39. 39.
    Garcia D, Shaw RJ 2017. AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell 66:789–800
     [Google Scholar]
  40. 40.
    Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ et al. 1996. Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem. 271:611–14
     [Google Scholar]
  41. 41.
    Konter JM, Parker JL, Baez E, Li SZ, Ranscht B et al. 2012. Adiponectin attenuates lipopolysaccharide-induced acute lung injury through suppression of endothelial cell activation. J. Immunol. 188:854–63
     [Google Scholar]
  42. 42.
    Shah D, Romero F, Duong M, Wang N, Paudyal B et al. 2015. Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury. Sci. Rep. 5:11362
     [Google Scholar]
  43. 43.
    Zhao X, Zmijewski JW, Lorne E, Liu G, Park YJ et al. 2008. Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 295:L497–504
     [Google Scholar]
  44. 44.
    Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT et al. 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–58
     [Google Scholar]
  45. 45.
    Heitman J, Movva NR, Hall MN 1991. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905–9
     [Google Scholar]
  46. 46.
    Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH 1994. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43
     [Google Scholar]
  47. 47.
    Saxton RA, Sabatini DM 2017. mTOR signaling in growth, metabolism, and disease. Cell 169:361–71
     [Google Scholar]
  48. 48.
    McCormack FX, Inoue Y, Moss J, Singer LG, Strange C et al. 2011. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N. Engl. J. Med. 364:1595–606
     [Google Scholar]
  49. 49.
    Ge J, Cui H, Xie N, Banerjee S, Guo S et al. 2018. Glutaminolysis promotes collagen translation and stability via α-ketoglutarate-mediated mTOR activation and proline hydroxylation. Am. J. Respir. Cell Mol. Biol. 58:378–90
     [Google Scholar]
  50. 50.
    Houssaini A, Adnot S 2017. mTOR: A key to both pulmonary vessel remodeling and right ventricular function in pulmonary arterial hypertension?. Am. J. Respir. Cell Mol. Biol. 57:509–11
     [Google Scholar]
  51. 51.
    Houssaini A, Breau M, Kebe K, Abid S, Marcos E et al. 2018. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight 3:e93203
     [Google Scholar]
  52. 52.
    Galluzzi L, Pietrocola F, Levine B, Kroemer G 2014. Metabolic control of autophagy. Cell 159:1263–76
     [Google Scholar]
  53. 53.
    Cloonan SM, Lam HC, Ryter SW, Choi AM 2014. “Ciliophagy”: the consumption of cilia components by autophagy. Autophagy 10:532–34
     [Google Scholar]
  54. 54.
    Levine B, Kroemer G 2008. Autophagy in the pathogenesis of disease. Cell 132:27–42
     [Google Scholar]
  55. 55.
    Chen ZH, Lam HC, Jin Y, Kim HP, Cao J et al. 2010. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. PNAS 107:18880–85
     [Google Scholar]
  56. 56.
    Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P et al. 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:121–34
     [Google Scholar]
  57. 57.
    Martinez-Vicente M, Cuervo AM 2007. Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 6:352–61
     [Google Scholar]
  58. 58.
    Rabinovitch M. 2012. Molecular pathogenesis of pulmonary arterial hypertension. J. Clin. Investig. 122:4306–13
     [Google Scholar]
  59. 59.
    Zank DC, Bueno M, Mora AL, Rojas M 2018. Idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics. Front. Med. 5:10
     [Google Scholar]
  60. 60.
    Barnes PJ, Burney PG, Silverman EK, Celli BR, Vestbo J et al. 2015. Chronic obstructive pulmonary disease. Nat. Rev. Dis. Primers 1:15076
     [Google Scholar]
  61. 61.
    Michaeloudes C, Kuo CH, Haji G, Finch DK, Halayko AJ et al. 2017. Metabolic re-patterning in COPD airway smooth muscle cells. Eur. Respir. J. 50:1700202
     [Google Scholar]
  62. 62.
    Coxson HO, Chan IH, Mayo JR, Hlynsky J, Nakano Y, Birmingham CL 2004. Early emphysema in patients with anorexia nervosa. Am. J. Respir. Crit. Care Med. 170:748–52
     [Google Scholar]
  63. 63.
    Sahebjami H, Wirman JA 1981. Emphysema-like changes in the lungs of starved rats. Am. Rev. Respir. Dis. 124:619–24
     [Google Scholar]
  64. 64.
    Stein J, Fenigstein H 1979. Pathological anatomy of hunger disease. Curr. Concepts Nutr. 7:207–34
     [Google Scholar]
  65. 65.
    Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M et al. 2014. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Investig. 124:3987–4003
     [Google Scholar]
  66. 66.
    Yaghi A, Dolovich MB 2016. Airway epithelial cell cilia and obstructive lung disease. Cells 5:40
     [Google Scholar]
  67. 67.
    DeMeo DL, Mariani T, Bhattacharya S, Srisuma S, Lange C et al. 2009. Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am. J. Hum. Genet. 85:493–502
     [Google Scholar]
  68. 68.
    Ito S, Araya J, Kurita Y, Kobayashi K, Takasaka N et al. 2015. PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis. Autophagy 11:547–59
     [Google Scholar]
  69. 69.
    Lam HC, Cloonan SM, Bhashyam AR, Haspel JA, Singh A et al. 2013. Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. J. Clin. Investig. 123:5212–30
     [Google Scholar]
  70. 70.
    Kirkham PA, Barnes PJ 2013. Oxidative stress in COPD. Chest 144:266–73
     [Google Scholar]
  71. 71.
    Zinellu E, Zinellu A, Fois AG, Carru C, Pirina P 2016. Circulating biomarkers of oxidative stress in chronic obstructive pulmonary disease: a systematic review. Respir. Res. 17:150
     [Google Scholar]
  72. 72.
    Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZC et al. 2017. Genetic control of fatty acid β-oxidation in chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 56:738–48
     [Google Scholar]
  73. 73.
    Yun JH, Morrow J, Owen CA, Qiu W, Glass K et al. 2017. Transcriptomic analysis of lung tissue from cigarette smoke-induced emphysema murine models and human chronic obstructive pulmonary disease show shared and distinct pathways. Am. J. Respir. Cell Mol. Biol. 57:47–58
     [Google Scholar]
  74. 74.
    Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM et al. 2015. Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J 29:2912–29
     [Google Scholar]
  75. 75.
    Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA et al. 2016. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23:303–14
     [Google Scholar]
  76. 76.
    Nyunoya T, Mebratu Y, Contreras A, Delgado M, Chand HS, Tesfaigzi Y 2014. Molecular processes that drive cigarette smoke-induced epithelial cell fate of the lung. Am. J. Respir. Cell Mol. Biol. 50:471–82
     [Google Scholar]
  77. 77.
    Barnes PJ. 2017. Senescence in COPD and its comorbidities. Annu. Rev. Physiol. 79:517–39
     [Google Scholar]
  78. 78.
    Fanta CH. 2009. Asthma. N. Engl. J. Med. 360:1002–14
     [Google Scholar]
  79. 79.
    McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ 2017. Diagnosis and management of asthma in adults: a review. JAMA 318:279–90
     [Google Scholar]
  80. 80.
    Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON et al. 2014. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 371:1189–97
     [Google Scholar]
  81. 81.
    Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV et al. 2011. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365:1088–98
     [Google Scholar]
  82. 82.
    Mushaben EM, Kramer EL, Brandt EB, Khurana Hershey GK, Le Cras TD 2011. Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma. J. Immunol. 187:5756–63
     [Google Scholar]
  83. 83.
    Zhang Y, Jing Y, Qiao J, Luan B, Wang X et al. 2017. Activation of the mTOR signaling pathway is required for asthma onset. Sci. Rep. 7:4532
     [Google Scholar]
  84. 84.
    Lloyd CM, Hawrylowicz CM 2009. Regulatory T cells in asthma. Immunity 31:438–49
     [Google Scholar]
  85. 85.
    Ostroukhova M, Seguin-Devaux C, Oriss TB, Dixon-McCarthy B, Yang L et al. 2004. Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3. J. Clin. Investig. 114:28–38
     [Google Scholar]
  86. 86.
    Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ et al. 2011. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186:3299–303
     [Google Scholar]
  87. 87.
    Shi LZ, Wang R, Huang G, Vogel P, Neale G et al. 2011. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208:1367–76
     [Google Scholar]
  88. 88.
    Park CS, Bang BR, Kwon HS, Moon KA, Kim TB et al. 2012. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem. Pharmacol. 84:1660–70
     [Google Scholar]
  89. 89.
    Pendharkar S, Mehta S 2008. The clinical significance of exhaled nitric oxide in asthma. Can. Respir. J. 15:99–106
     [Google Scholar]
  90. 90.
    Xu W, Ghosh S, Comhair SA, Asosingh K, Janocha AJ et al. 2016. Increased mitochondrial arginine metabolism supports bioenergetics in asthma. J. Clin. Investig. 126:2465–81
     [Google Scholar]
  91. 91.
    Li H, Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, Estela Del Rio-Navarro B et al. 2006. Genetic polymorphisms in arginase I and II and childhood asthma and atopy. J Allergy Clin. Immunol. 117:119–26
     [Google Scholar]
  92. 92.
    Vonk JM, Postma DS, Maarsingh H, Bruinenberg M, Koppelman GH, Meurs H 2010. Arginase 1 and arginase 2 variations associate with asthma, asthma severity and β2 agonist and steroid response. Pharmacogenet. Genom. 20:179–86
     [Google Scholar]
  93. 93.
    Trian T, Benard G, Begueret H, Rossignol R, Girodet PO et al. 2007. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J. Exp. Med. 204:3173–81
     [Google Scholar]
  94. 94.
    Roth M, Johnson PR, Borger P, Bihl MP, Rudiger JJ et al. 2004. Dysfunctional interaction of C/EBPα and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N. Engl. J. Med. 351:560–74
     [Google Scholar]
  95. 95.
    Cheng Z, Wang X, Dai L, Jia L, Jing X et al. 2017. Suppression of microRNA-384 enhances autophagy of airway smooth muscle cells in asthmatic mouse. Oncotarget 8:67933–41
     [Google Scholar]
  96. 96.
    Pan S, Sharma P, Shah SD, Deshpande DA 2017. Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 313:L154–65
     [Google Scholar]
  97. 97.
    Wolters PJ, Collard HR, Jones KD 2014. Pathogenesis of idiopathic pulmonary fibrosis. Annu. Rev. Pathol. Mech. Dis. 9:157–79
     [Google Scholar]
  98. 98.
    Gross TJ, Hunninghake GW 2001. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 345:517–25
     [Google Scholar]
  99. 99.
    Sisson TH, Mendez M, Choi K, Subbotina N, Courey A et al. 2010. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 181:254–63
     [Google Scholar]
  100. 100.
    Kang YP, Lee SB, Lee JM, Kim HM, Hong JY et al. 2016. Metabolic profiling regarding pathogenesis of idiopathic pulmonary fibrosis. J. Proteome Res. 15:1717–24
     [Google Scholar]
  101. 101.
    Bueno M, Lai YC, Romero Y, Brands J, St Croix CM et al. 2015. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin. Investig. 125:521–38
     [Google Scholar]
  102. 102.
    Yu G, Tzouvelekis A, Wang R, Herazo-Maya JD, Ibarra GH et al. 2018. Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat. Med. 24:39–49
     [Google Scholar]
  103. 103.
    Romero F, Shah D, Duong M, Penn RB, Fessler MB et al. 2015. A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis. Am. J. Respir. Cell Mol. Biol. 53:74–86
     [Google Scholar]
  104. 104.
    Kottmann RM, Kulkarni AA, Smolnycki KA, Lyda E, Dahanayake T et al. 2012. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β. Am. J. Respir. Crit. Care Med. 186:740–51
     [Google Scholar]
  105. 105.
    Burman A, Tanjore H, Blackwell TS 2018. Endoplasmic reticulum stress in pulmonary fibrosis. Matrix Biol 68–69:355–65
     [Google Scholar]
  106. 106.
    Lenna S, Trojanowska M 2012. The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis. Curr. Opin. Rheumatol. 24:663–68
     [Google Scholar]
  107. 107.
    Xu Y, Mizuno T, Sridharan A, Du Y, Guo M et al. 2016. Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis. JCI Insight 1:e90558
     [Google Scholar]
  108. 108.
    Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW et al. 2018. Metformin reverses established lung fibrosis in a bleomycin model. Nat. Med. 24:1121–27
     [Google Scholar]
  109. 109.
    Xie N, Tan Z, Banerjee S, Cui H, Ge J et al. 2015. Glycolytic reprogramming in myofibroblast differentiation and lung fibrosis. Am. J. Respir. Crit. Care Med. 192:1462–74
     [Google Scholar]
  110. 110.
    Cho SJ, Moon JS, Lee CM, Choi AM, Stout-Delgado HW 2017. Glucose transporter 1-dependent glycolysis is increased during aging-related lung fibrosis, and phloretin inhibits lung fibrosis. Am. J. Respir. Cell Mol. Biol. 56:521–31
     [Google Scholar]
  111. 111.
    Goodwin J, Choi H, Hsieh MH, Neugent ML, Ahn JM et al. 2018. Targeting hypoxia-inducible factor-1α/pyruvate dehydrogenase kinase 1 axis by dichloroacetate suppresses bleomycin-induced pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 58:216–31
     [Google Scholar]
  112. 112.
    Dunbar EM, Coats BS, Shroads AL, Langaee T, Lew A et al. 2014. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Investig. New Drugs 32:452–64
     [Google Scholar]
  113. 113.
    Hamanaka RB, Nigdelioglu R, Meliton AY, Tian Y, Witt LJ et al. 2018. Inhibition of phosphoglycerate dehydrogenase attenuates bleomycin-induced pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 58:585–93
     [Google Scholar]
  114. 114.
    Nigdelioglu R, Hamanaka RB, Meliton AY, O'Leary E, Witt LJ et al. 2016. Transforming growth factor (TGF)-β promotes de novo serine synthesis for collagen production. J. Biol. Chem. 291:27239–51
     [Google Scholar]
  115. 115.
    Bernard K, Logsdon NJ, Benavides GA, Sanders Y, Zhang J et al. 2018. Glutaminolysis is required for transforming growth factor-β1-induced myofibroblast differentiation and activation. J. Biol. Chem. 293:1218–28
     [Google Scholar]
  116. 116.
    Xie N, Cui H, Ge J, Banerjee S, Guo S et al. 2017. Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 313:L834–44
     [Google Scholar]
  117. 117.
    Galván-Peña S, O'Neill LAJ 2014. Metabolic reprograming in macrophage polarization. Front. Immunol. 5:420
     [Google Scholar]
  118. 118.
    Farber HW, Loscalzo J 2004. Pulmonary arterial hypertension. N. Engl. J. Med. 351:1655–65
     [Google Scholar]
  119. 119.
    D'Alessandro A, El Kasmi KC, Plecitá-Hlavatá L, Ježek P, Li M et al. 2018. Hallmarks of pulmonary hypertension: mesenchymal and inflammatory cell metabolic reprogramming. Antioxid. Redox Signal. 28:230–50
     [Google Scholar]
  120. 120.
    Tuder RM, Davis LA, Graham BB 2012. Targeting energetic metabolism: a new frontier in the pathogenesis and treatment of pulmonary hypertension. Am. J. Respir. Crit. Care Med. 185:260–66
     [Google Scholar]
  121. 121.
    Fessel JP, Hamid R, Wittmann BM, Robinson LJ, Blackwell T et al. 2012. Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming. Pulm Circ 2:201–13
     [Google Scholar]
  122. 122.
    Sutendra G, Michelakis ED 2014. The metabolic basis of pulmonary arterial hypertension. Cell Metab 19:558–73
     [Google Scholar]
  123. 123.
    Stenmark KR, Tuder RM, El Kasmi KC 2015. Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension. J. Appl. Physiol. 119:1164–72
     [Google Scholar]
  124. 124.
    Plecitá-Hlavatá L, Tauber J, Li M, Zhang H, Flockton AR et al. 2016. Constitutive reprogramming of fibroblast mitochondrial metabolism in pulmonary hypertension. Am. J. Respir. Cell Mol. Biol. 55:47–57
     [Google Scholar]
  125. 125.
    Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q et al. 2009. Function of mitochondrial Stat3 in cellular respiration. Science 323:793–97
     [Google Scholar]
  126. 126.
    Masri FA, Xu W, Comhair SA, Asosingh K, Koo M et al. 2007. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 293:L548–54
     [Google Scholar]
  127. 127.
    Paulin R, Meloche J, Jacob MH, Bisserier M, Courboulin A, Bonnet S 2011. Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol. 301:H1798–809
     [Google Scholar]
  128. 128.
    Diebold I, Hennigs JK, Miyagawa K, Li CG, Nickel NP et al. 2015. BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab 21:596–608
     [Google Scholar]
  129. 129.
    Paulin R, Dromparis P, Sutendra G, Gurtu V, Zervopoulos S et al. 2014. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab 20:827–39
     [Google Scholar]
  130. 130.
    McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A et al. 2004. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 95:830–40
     [Google Scholar]
  131. 131.
    Michelakis ED, Gurtu V, Webster L, Barnes G, Watson G et al. 2017. Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Sci. Transl. Med. 9:eaao4583
     [Google Scholar]
  132. 132.
    Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R et al. 2002. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105:244–50
     [Google Scholar]
  133. 133.
    Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ et al. 2012. Lung 18F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 185:670–79
     [Google Scholar]
  134. 134.
    Haslip M, Dostanic I, Huang Y, Zhang Y, Russell KS et al. 2015. Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension during intermittent hypoxia. Arterioscler. Thromb. Vasc. Biol. 35:1166–78
     [Google Scholar]
  135. 135.
    Pak O, Sommer N, Hoeres T, Bakr A, Waisbrod S et al. 2013. Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model. Am. J. Respir. Cell Mol. Biol. 49:358–67
     [Google Scholar]
  136. 136.
    Dyck JR, Hopkins TA, Bonnet S, Michelakis ED, Young ME et al. 2006. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation 114:1721–28
     [Google Scholar]
  137. 137.
    Zhang Y, Sauler M, Shinn AS, Gong H, Haslip M et al. 2014. Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury. J. Immunol. 192:5296–304
     [Google Scholar]
  138. 138.
    Bertero T, Cottrill KA, Lu Y, Haeger CM, Dieffenbach P et al. 2015. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Rep 13:1016–32
     [Google Scholar]
  139. 139.
    Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR et al. 2016. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J. Clin. Investig. 126:3313–35
     [Google Scholar]
  140. 140.
    Mathis D, Shoelson SE 2011. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11:81
     [Google Scholar]
  141. 141.
    Yin Y, Choi SC, Xu Z, Perry DJ, Seay H et al. 2015. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl. Med. 7:274ra18
     [Google Scholar]
/content/journals/10.1146/annurev-physiol-020518-114640
Loading
Cellular Metabolism in Lung Health and Disease
Annual Review of Physiology 81, 403 (2019); https://doi.org/10.1146/annurev-physiol-020518-114640
/content/journals/10.1146/annurev-physiol-020518-114640
/content/journals/10.1146/annurev-physiol-020518-114640
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error