1932

Abstract

Remarkable new roles for mitochondria in calcium handling, apoptosis, heme turnover, inflammation, and oxygen and nutrient sensing have been discovered for organelles that were once thought to be simple energy converters. Although deficits in mitochondrial function are often associated with energy failure and apoptosis, working cells maintain a mitochondrial reserve that affords the organelles distinct homeostatic sensing and regulatory abilities in lung cells. As primary intracellular sources of oxidants, mitochondria serve as critical monitors and modulators of vital oxidation-reduction processes, including mitochondrial biogenesis, mitophagy, inflammasome activation, cell proliferation, and prevention of fibrosis. These processes participate in disease pathogenesis in all lung regions mainly when interference with mitochondrial quality control mechanisms impedes their roles in maintenance of lung health. Sharper identification of mitochondrial-driven signaling mechanisms in specific lung cell types will better refine our understanding of respiratory disease pathogenesis and lead to new diagnostic and therapeutic measures to support mitochondrial quality.

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2017-02-10
2024-03-29
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Literature Cited

  1. Shadel GS, Horvath TL. 1.  2015. Mitochondrial ROS signaling in organismal homeostasis. Cell 163:3560–69 [Google Scholar]
  2. Piantadosi CA, Suliman HB. 2.  2012. Transcriptional control of mitochondrial biogenesis and its interface with inflammatory processes. Biochim. Biophys. Acta 1820:4532–41 [Google Scholar]
  3. Vartak R, Porras CA, Bai Y. 3.  2013. Respiratory supercomplexes: structure, function and assembly. Protein Cell 4:8582–90 [Google Scholar]
  4. Ikeda K, Shiba S, Horie-Inoue K, Shimokata K, Inoue S. 4.  2013. A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle. Nat. Commun. 4:2147 [Google Scholar]
  5. Gail DB, Lenfant CJ. 5.  1983. Cells of the lung: biology and clinical implications. Am. Rev. Respir. Dis. 127:3366–87 [Google Scholar]
  6. Fisher AB, Steinberg H, Bassett D. 6.  1974. Energy utilization by the lung. Am. J. Med. 57:3437–46 [Google Scholar]
  7. Williamson JR, Corkey BE. 7.  1979. Assay of citric acid cycle intermediates and related compounds—update with tissue metabolite levels and intracellular distribution. Methods Enzymol 55:200–22 [Google Scholar]
  8. Mustafa MG, Cross CE. 8.  1974. Effects of short-term ozone exposure on lung mitochondrial oxidative and energy metabolism. Arch. Biochem. Biophys. 162:2585–94 [Google Scholar]
  9. Hüttemann M, Lee I, Gao X, Pecina P, Pecinova A. 9.  et al. 2012. Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology. FASEB J 26:93916–30 [Google Scholar]
  10. Carraway MS, Suliman HB, Kliment C, Welty-Wolf KE, Oury TD, Piantadosi CA. 10.  2008. Mitochondrial biogenesis in the pulmonary vasculature during inhalational lung injury and fibrosis. Antioxid. Redox Signal. 10:2269–75 [Google Scholar]
  11. Zou C, Synan MJ, Li J, Xiong S, Manni ML. 11.  et al. 2016. LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J. Cell Sci. 129:151–64 [Google Scholar]
  12. Massaro GD, Gail DB, Massaro D. 12.  1975. Lung oxygen consumption and mitochondria of alveolar epithelial and endothelial cells. J. Appl. Physiol. 38:4588–92 [Google Scholar]
  13. Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR. 13.  et al. 2013. Type 2 alveolar cells are stem cells in adult lung. J. Clin. Investig. 123:73025–36 [Google Scholar]
  14. Moriguchi K, Higashi N, Kitagawa S, Takase K, Ohya N. 14.  et al. 1984. Differentiation of human pulmonary alveolar epithelial cells revealed by peroxisome changes in pulmonary proteinosis. Exp. Mol. Pathol. 40:2262–70 [Google Scholar]
  15. Hirai K, Ogawa K. 15.  1986. Cytochemical quantitation of cytochrome oxidase activity in rat pulmonary alveolar epithelial cells and possible defect in type I cells. J. Electron. Microsc. 35:119–28 [Google Scholar]
  16. Schumacker PT, Gillespie MN, Nakahira K, Choi AM, Crouser ED. 16.  et al. 2014. Mitochondria in lung biology and pathology: more than just a powerhouse. Am. J. Physiol. Lung. Cell Mol. Physiol. 306:11L962–74 [Google Scholar]
  17. Nunnari J, Suomalainen A. 17.  2012. Mitochondria: in sickness and in health. Cell 148:61145–59 [Google Scholar]
  18. Cha MY, Kim DK, Mook-Jung I. 18.  2015. The role of mitochondrial DNA mutation on neurodegenerative diseases. Exp. Mol. Med. 47:e150 [Google Scholar]
  19. Liu TF, Vachharajani V, Millet P, Bharadwaj MS, Molina AJ, McCall CE. 19.  2015. Sequential actions of SIRT1-RELB-SIRT3 coordinate nuclear-mitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis. J. Biol. Chem. 290:1396–408 [Google Scholar]
  20. Zhou R, Yazdi AS, Menu P, Tschopp J. 20.  2011. A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–25 [Google Scholar]
  21. Gu X, Wu G, Yao Y, Zeng J, Shi D. 21.  et al. 2015. Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway. Free Radic. Biol. Med. 83:149–58 [Google Scholar]
  22. Block K, Gorin Y, Abboud HE. 22.  2009. Subcellular localization of Nox4 and regulation in diabetes. PNAS 106:3414385–90 [Google Scholar]
  23. Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J. 23.  2010. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circ. Res. 106:71253–64 [Google Scholar]
  24. Dranka BP, Hill BG, Darley-Usmar VM. 24.  2010. Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radic. Biol. Med. 48:7905–14 [Google Scholar]
  25. Chandel NS. 25.  2014. Mitochondria as signaling organelles. BMC Biol 12:34 [Google Scholar]
  26. Rizzuto R, De Stefani D, Raffaello A, Mammucari C. 26.  2012. Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell Biol. 13:9566–78 [Google Scholar]
  27. Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S. 27.  et al. 2006. Mitochondrial dynamics and Ca2+ signaling. Biochim. Biophys. Acta 1763:5–6442–49 [Google Scholar]
  28. Dromparis P, Michelakis ED. 28.  2013. Mitochondria in vascular health and disease. Annu. Rev. Physiol. 75:95–126 [Google Scholar]
  29. Kleine T, Leister D. 29.  2016. Retrograde signaling: organelles go networking. Biochim. Biophys. Acta 1857:1313–25 [Google Scholar]
  30. Sena LA, Chandel NS. 30.  2012. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48:2158–67 [Google Scholar]
  31. Metallo CM, Vander Heiden MG. 31.  2010. Metabolism strikes back: metabolic flux regulates cell signaling. Genes Dev 24:242717–22 [Google Scholar]
  32. Kaelin WG Jr., McKnight SL. 32.  2013. Influence of metabolism on epigenetics and disease. Cell 153:156–69 [Google Scholar]
  33. Pearce EL, Poffenberger MC, Chang CH, Jones RG. 33.  2013. Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454 [Google Scholar]
  34. Gazdhar A, Lebrecht D, Roth M, Tamm M, Venhoff N. 34.  et al. 2014. Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis. Sci. Rep. 4:5336 [Google Scholar]
  35. Green DR, Llambi F. 35.  2015. Cell death signaling. Cold Spring Harb. Perspect. Biol. 7:12a006080 [Google Scholar]
  36. Santos JH, Hunakova L, Chen Y, Bortner C, Van Houten B. 36.  2003. Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death. J. Biol. Chem. 278:31728–34 [Google Scholar]
  37. Bueno M, Lai YC, Romero Y, Brands J, St. Croix CM. 37.  et al. 2015. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J. Clin. Investig. 125:2521–38 [Google Scholar]
  38. Buder-Hoffmann SA, Shukla A, Barrett TF, MacPherson MB, Lounsbury KM, Mossman BT. 38.  2009. A protein kinase C∂-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos. Am. J. Pathol. 174:2449–59 [Google Scholar]
  39. Lounsbury KM, Stern M, Taatjes D, Jaken S, Mossman BT. 39.  2002. Increased localization and substrate activation of protein kinase C∂ in lung epithelial cells following exposure to asbestos. Am. J. Pathol. 160:61991–2000 [Google Scholar]
  40. Jornayvaz FR, Shulman GI. 40.  2010. Regulation of mitochondrial biogenesis. Essays Biochem 47:69–84 [Google Scholar]
  41. Athale J, Ulrich A, MacGarvey NC, Bartz RR, Welty-Wolf KE. 41.  et al. 2012. Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice. Free Radic. Biol. Med. 53:81584–94 [Google Scholar]
  42. Scarpulla RC. 42.  2008. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88:2611–38 [Google Scholar]
  43. Suliman HB, Carraway MS, Tatro LG, Piantadosi CA. 43.  2007. A new activating role for CO in cardiac mitochondrial biogenesis. J. Cell Sci. 120:Pt. 2299–308 [Google Scholar]
  44. Terman A, Kurz T, Navratil M, Arriaga EA, Brunk UT. 44.  2010. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid. Redox Signal. 12:4503–35 [Google Scholar]
  45. Haynes CM, Ron D. 45.  2010. The mitochondrial UPR-protecting organelle protein homeostasis. J. Cell Sci. 123:Pt. 223849–55 [Google Scholar]
  46. Lee J, Giordano S, Zhang J. 46.  2012. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J. 441:2523–40 [Google Scholar]
  47. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P. 47.  et al. 2010. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11:145–51 [Google Scholar]
  48. Liu L, Feng D, Chen G, Chen M, Zheng Q. 48.  et al. 2012. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat. Cell Biol. 14:2177–85 [Google Scholar]
  49. Ding WX, Ni HM, Li M, Liao Y, Chen X. 49.  et al. 2010. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J. Biol. Chem. 285:3627879–90 [Google Scholar]
  50. Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ. 50.  et al. 2011. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20:91726–37 [Google Scholar]
  51. Yoshii SR, Kishi C, Ishihara N, Mizushima N. 51.  2011. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J. Biol. Chem. 286:2219630–40 [Google Scholar]
  52. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC. 52.  et al. 2010. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12:2119–31 [Google Scholar]
  53. Narendra D, Tanaka A, Suen DF, Youle RJ. 53.  2008. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183:5795–803 [Google Scholar]
  54. Mao K, Wang K, Liu X, Klionsky DJ. 54.  2013. The scaffold protein Atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. Dev. Cell 26:19–18 [Google Scholar]
  55. Twig G, Hyde B, Shirihai OS. 55.  2008. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim. Biophys. Acta 1777:91092–97 [Google Scholar]
  56. Egan D, Kim J, Shaw RJ, Guan KL. 56.  2011. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7:6643–44 [Google Scholar]
  57. Suliman HB, Carraway MS, Piantadosi CA. 57.  2003. Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am. J. Respir. Crit. Care Med. 167:4570–79 [Google Scholar]
  58. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T. 58.  et al. 2010. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–7 [Google Scholar]
  59. Sun S, Sursal T, Adibnia Y, Zhao C, Zheng Y. 59.  et al. 2013. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLOS ONE 8:3e59989 [Google Scholar]
  60. Medzhitov R. 60.  2007. Recognition of microorganisms and activation of the immune response. Nature 449:819–26 [Google Scholar]
  61. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H. 61.  et al. 2011. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472:7344476–80 [Google Scholar]
  62. Collins LV, Hajizadeh S, Holme E, Jonsson IM, Tarkowski A. 62.  2004. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75:6995–1000 [Google Scholar]
  63. Hou Q, Jin J, Zhou H, Novgorodov SA, Bielawska A. 63.  et al. 2011. Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J. Lipid Res. 52:2278–88 [Google Scholar]
  64. Zhao Y, Sun X, Nie X, Sun L, Tang TS. 64.  et al. 2012. COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLOS Pathog 8:12e1003086 [Google Scholar]
  65. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. 65.  2013. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153:2348–61 [Google Scholar]
  66. Chang CH, Curtis JD, Maggi LB Jr., Faubert B, Villarino AV. 66.  et al. 2013. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:61239–51 [Google Scholar]
  67. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T. 67.  et al. 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12:3222–30 [Google Scholar]
  68. Suliman HB, Piantadosi CA. 68.  2014. Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress. Curr. Pharm. Des. 20:355653–62 [Google Scholar]
  69. Chang AL, Ulrich A, Suliman HB, Piantadosi CA. 69.  2015. Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis. Free Radic. Biol. Med. 78:179–89 [Google Scholar]
  70. Suliman HB, Piantadosi CA. 70.  2016. Mitochondrial quality control as a therapeutic target. Pharmacol. Rev. 68:120–48 [Google Scholar]
  71. Hotchkiss RS, Karl IE. 71.  2003. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348:2138–50 [Google Scholar]
  72. Galley HF. 72.  2011. Oxidative stress and mitochondrial dysfunction in sepsis. Br. J. Anaesth. 107:157–64 [Google Scholar]
  73. Cash TP, Pan Y, Simon MC. 73.  2007. Reactive oxygen species and cellular oxygen sensing. Free Radic. Biol. Med. 43:91219–25 [Google Scholar]
  74. Singer M. 74.  2014. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5:166–72 [Google Scholar]
  75. Haden DW, Suliman HB, Carraway MS, Welty-Wolf KE, Ali AS. 75.  et al. 2007. Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am. J. Respir. Crit. Care Med. 176:8768–77 [Google Scholar]
  76. Rasbach KA, Schnellmann RG. 76.  2007. Signaling of mitochondrial biogenesis following oxidant injury. J. Biol. Chem. 282:42355–62 [Google Scholar]
  77. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S. 77.  et al. 2014. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20:111327–33 [Google Scholar]
  78. West AP, Shadel GS, Ghosh S. 78.  2011. Mitochondria in innate immune responses. Nat. Rev. Immunol. 11:6389–402 [Google Scholar]
  79. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL. 79.  et al. 2006. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation. Cell Metab 4:113–24 [Google Scholar]
  80. Islam MN, Das SR, Emin MT, Wei M, Sun L. 80.  et al. 2012. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 18:5759–65 [Google Scholar]
  81. Finkel T, Menazza S, Holmström KM, Parks RJ, Liu J. 81.  et al. 2015. The ins and outs of mitochondrial calcium. Circ. Res. 116:111810–19 [Google Scholar]
  82. Ichinohe T, Yamazaki T, Koshiba T, Yanagi Y. 82.  2013. Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection. PNAS 110:4417963–68 [Google Scholar]
  83. Haslip M, Dostanic I, Huang Y, Zhang Y, Russell KS. 83.  et al. 2015. Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension during intermittent hypoxia. Arterioscler. Thromb. Vasc. Biol. 35:51166–78 [Google Scholar]
  84. Cero FT, Hillestad V, Sjaastad I, Yndestad A, Aukrust P. 84.  et al. 2015. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am. J. Physiol. Lung. Cell Mol. Physiol. 309:4L378–87 [Google Scholar]
  85. Goritzka M, Makris S, Kausar F, Durant LR, Pereira C. 85.  et al. 2015. Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J. Exp. Med. 212:5699–714 [Google Scholar]
  86. Berkelhamer SK, Kim GA, Radder JE, Wedgwood S, Czech L. 86.  et al. 2013. Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung. Free Radic. Biol. Med. 61:51–60 [Google Scholar]
  87. Sureshbabu A, Bhandari V. 87.  2013. Targeting mitochondrial dysfunction in lung diseases: emphasis on mitophagy. Front. Physiol. 4:384 [Google Scholar]
  88. Otsubo C, Bharathi S, Uppala R, Ilkayeva OR, Wang D. 88.  et al. 2015. Long-chain acylcarnitines reduce lung function by inhibiting pulmonary surfactant. J. Biol. Chem. 290:3923897–904 [Google Scholar]
  89. Mannam P, Shinn AS, Srivastava A, Neamu RF, Walker WE. 89.  et al. 2014. MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. Am. J. Physiol. Lung. Cell Mol. Physiol. 306:7L604–19 [Google Scholar]
  90. Chen BB, Coon TA, Glasser JR, Zou C, Ellis B. 90.  et al. 2014. E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia. Cell Rep 7:2476–87 [Google Scholar]
  91. Alsuwaidi AR, Benedict S, Kochiyil J, Mustafa F, Hartwig SM. 91.  et al. 2013. Bioenergetics of murine lungs infected with respiratory syncytial virus. Virol. J. 10:22 [Google Scholar]
  92. Hood DA. 92.  2001. Invited review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J. Appl. Physiol. 90:31137–57 [Google Scholar]
  93. Kirkham PA, Barnes PJ. 93.  2013. Oxidative stress in COPD. Chest 144:1266–73 [Google Scholar]
  94. Meyer A, Zoll J, Charles AL, Charloux A, de Blay F. 94.  et al. 2013. Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target. Exp. Physiol. 98:61063–78 [Google Scholar]
  95. Lloreta J, Orozco M, Gea J, Corominas JM, Serrano S. 95.  1996. Selective diaphragmatic mitochondrial abnormalities in a patient with marked air flow obstruction. Ultrastruct. Pathol. 20:167–71 [Google Scholar]
  96. van der Toorn M, Slebos DJ, de Bruin HG, Leuvenink HG, Bakker SJ. 96.  et al. 2007. Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis. Am. J. Physiol. Lung. Cell Mol. Physiol. 292:5L1211–18 [Google Scholar]
  97. Verhamme FM, Bracke KR, Joos GF, Brusselle GG. 97.  2015. Transforming growth factor-β superfamily in obstructive lung diseases. More suspects than TGF-β alone. Am. J. Respir. Cell Mol. Biol. 52:6653–62 [Google Scholar]
  98. Kang C, Li Ji L. 98.  2012. Role of PGC-1α signaling in skeletal muscle health and disease. Ann. N.Y. Acad. Sci. 1271:110–17 [Google Scholar]
  99. Cherry AD, Suliman HB, Bartz RR, Piantadosi CA. 99.  2014. Peroxisome proliferator-activated receptor gamma co-activator 1-α as a critical co-activator of the murine hepatic oxidative stress response and mitochondrial biogenesis in Staphylococcus aureus sepsis. J. Biol. Chem. 289:141–52 [Google Scholar]
  100. Bocci V, Valacchi G. 100.  2015. Nrf2 activation as target to implement therapeutic treatments. Front. Chem. 3:4 [Google Scholar]
  101. Soulitzis N, Neofytou E, Psarrou M, Anagnostis A, Tavernarakis N. 101.  et al. 2012. Downregulation of lung mitochondrial prohibitin in COPD. Respir. Med. 106:7954–61 [Google Scholar]
  102. Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M. 102.  et al. 2014. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Investig. 124:93987–4003 [Google Scholar]
  103. Ito S, Araya J, Kurita Y, Kobayashi K, Takasaka N. 103.  et al. 2015. PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis. Autophagy 11:3547–59 [Google Scholar]
  104. Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM. 104.  et al. 2015. Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J 29:72912–29 [Google Scholar]
  105. Patel AS, Song JW, Chu SG, Mizumura K, Osorio JC. 105.  et al. 2015. Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis. PLOS ONE 10:3e0121246 [Google Scholar]
  106. Liu SF, Kuo HC, Tseng CW, Huang HT, Chen YC. 106.  et al. 2015. Leukocyte mitochondrial DNA copy number is associated with chronic obstructive pulmonary disease. PLOS ONE 10:9e0138716 [Google Scholar]
  107. Postma DS, Rabe KF. 107.  2015. The asthma-COPD overlap syndrome. N. Engl. J. Med. 373:131241–49 [Google Scholar]
  108. Zifa E, Daniil Z, Skoumi E, Stavrou M, Papadimitriou K. 108.  et al. 2012. Mitochondrial genetic background plays a role in increasing risk to asthma. Mol. Biol. Rep. 39:44697–708 [Google Scholar]
  109. Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I. 109.  2009. Mitochondrial dysfunction increases allergic airway inflammation. J. Immunol. 183:85379–87 [Google Scholar]
  110. Mabalirajan U, Dinda AK, Kumar S, Roshan R, Gupta P. 110.  et al. 2008. Mitochondrial structural changes and dysfunction are associated with experimental allergic asthma. J. Immunol. 181:53540–48 [Google Scholar]
  111. Aravamudan B, Kiel A, Freeman M, Delmotte P, Thompson M. 111.  et al. 2014. Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am. J. Physiol. Lung. Cell Mol. Physiol. 306:9L840–54 [Google Scholar]
  112. Aravamudan B, Thompson MA, Pabelick CM, Prakash YS. 112.  2013. Mitochondria in lung diseases. Expert. Rev. Respir. Med. 7:6631–46 [Google Scholar]
  113. Ahmad T, Mukherjee S, Pattnaik B, Kumar M, Singh S. 113.  et al. 2014. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J 33:9994–1010 [Google Scholar]
  114. Murthy S, Adamcakova-Dodd A, Perry SS, Tephly LA, Keller RM. 114.  et al. 2009. Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis. Am. J. Physiol. Lung. Cell Mol. Physiol. 297:5L846–55 [Google Scholar]
  115. Osborn-Heaford HL, Ryan AJ, Murthy S, Racila AM, He C. 115.  et al. 2012. Mitochondrial Rac1 GTPase import and electron transfer from cytochrome c are required for pulmonary fibrosis. J. Biol. Chem. 287:53301–12 [Google Scholar]
  116. Shukla A, Lounsbury KM, Barrett TF, Gell J, Rincon M. 116.  et al. 2007. Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-∂ knockout mice. Am. J. Pathol. 170:1140–51 [Google Scholar]
  117. Panduri V, Surapureddi S, Soberanes S, Weitzman SA, Chandel N, Kamp DW. 117.  2006. P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis. Am. J. Respir. Cell Mol. Biol. 34:4443–52 [Google Scholar]
  118. Eberle J, Hossini AM. 118.  2008. Expression and function of Bcl-2 proteins in melanoma. Curr. Genom. 9:6409–19 [Google Scholar]
  119. Antigny F, Girardin N, Raveau D, Frieden M, Becq F, Vandebrouck C. 119.  2009. Dysfunction of mitochondria Ca2+ uptake in cystic fibrosis airway epithelial cells. Mitochondrion 9:4232–41 [Google Scholar]
  120. Evans AM, Hardie DG, Peers C, Mahmoud A. 120.  2011. Hypoxic pulmonary vasoconstriction: mechanisms of oxygen-sensing. Curr. Opin. Anaesthesiol. 24:113–20 [Google Scholar]
  121. Kamdar O, Le W, Zhang J, Ghio AJ, Rosen GD, Upadhyay D. 121.  2008. Air pollution induces enhanced mitochondrial oxidative stress in cystic fibrosis airway epithelium. FEBS Lett 582:25–263601–6 [Google Scholar]
  122. Shapiro BL. 122.  1988. Mitochondrial dysfunction, energy expenditure, and cystic fibrosis. Lancet 2:8605289 [Google Scholar]
  123. Chomyn A. 123.  2001. Mitochondrial genetic control of assembly and function of complex I in mammalian cells. J. Bioenerg. Biomembr. 33:3251–57 [Google Scholar]
  124. Chatterjee A, Mambo E, Sidransky D. 124.  2006. Mitochondrial DNA mutations in human cancer. Oncogene 25:344663–74 [Google Scholar]
  125. Yang Ai SS, Hsu K, Herbert C, Cheng Z, Hunt J. 125.  et al. 2013. Mitochondrial DNA mutations in exhaled breath condensate of patients with lung cancer. Respir. Med. 107:6911–18 [Google Scholar]
  126. Kamp DW, Shacter E, Weitzman SA. 126.  2011. Chronic inflammation and cancer: the role of the mitochondria. Oncology 25:5400–10, 13 [Google Scholar]
  127. Aichler M, Elsner M, Ludyga N, Feuchtinger A, Zangen V. 127.  et al. 2013. Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria. J. Pathol. 230:4410–19 [Google Scholar]
  128. Kongara S, Karantza V. 128.  2012. The interplay between autophagy and ROS in tumorigenesis. Front. Oncol. 2:171 [Google Scholar]
  129. Dasgupta S, Soudry E, Mukhopadhyay N, Shao C, Yee J. 129.  et al. 2012. Mitochondrial DNA mutations in respiratory complex-I in never-smoker lung cancer patients contribute to lung cancer progression and associated with EGFR gene mutation. J. Cell Physiol. 227:62451–60 [Google Scholar]
  130. van Waveren C, Sun Y, Cheung HS, Moraes CT. 130.  2006. Oxidative phosphorylation dysfunction modulates expression of extracellular matrix–remodeling genes and invasion. Carcinogenesis 27:3409–18 [Google Scholar]
  131. Murphy MP, Smith RA. 131.  2000. Drug delivery to mitochondria: the key to mitochondrial medicine. Adv. Drug Deliv. Rev. 41:2235–50 [Google Scholar]
  132. Garber K. 132.  2012. Biochemistry: a radical treatment. Nature 489:S4–6 [Google Scholar]
  133. Harvey CJ, Thimmulappa RK, Sethi S, Kong X, Yarmus L. 133.  et al. 2011. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci. Transl. Med. 3:7878ra32 [Google Scholar]
  134. Zhu H, Jia Z, Strobl JS, Ehrich M, Misra HP, Li Y. 134.  2008. Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress. Cardiovasc. Toxicol. 8:3115–25 [Google Scholar]
  135. Geismann C, Arlt A, Sebens S, Schäfer H. 135.  2014. Cytoprotection “gone astray”: Nrf2 and its role in cancer. Onco. Targets Ther. 7:1497–518 [Google Scholar]
  136. Suliman HB, Welty-Wolf KE, Carraway M, Tatro L, Piantadosi CA. 136.  2004. Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc. Res. 64:2279–88 [Google Scholar]
  137. Piantadosi CA, Withers CM, Bartz RR, MacGarvey NC, Fu P. 137.  et al. 2011. Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J. Biol. Chem. 286:1816374–85 [Google Scholar]
  138. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C. 138.  et al. 2003. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299:896–99 [Google Scholar]
  139. Wang K, Klionsky DJ. 139.  2011. Mitochondria removal by autophagy. Autophagy 7:3297–300 [Google Scholar]
  140. Zhang J, Ney PA. 140.  2009. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16:7939–46 [Google Scholar]
  141. Aich J, Mabalirajan U, Ahmad T, Khanna K, Rehman R. 141.  et al. 2012. Resveratrol attenuates experimental allergic asthma in mice by restoring inositol polyphosphate 4 phosphatase (INPP4A). Int. Immunopharmacol. 14:4438–43 [Google Scholar]
  142. Mabalirajan U, Ahmad T, Leishangthem GD, Dinda AK, Agrawal A, Ghosh B. 142.  2010. L-arginine reduces mitochondrial dysfunction and airway injury in murine allergic airway inflammation. Int. Immunopharmacol. 10:121514–19 [Google Scholar]
  143. Calixto MC, Lintomen L, André DM, Leiria LO, Ferreira D. 143.  et al. 2013. Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet-induced obesity in mice. PLOS ONE 8:10e76786 [Google Scholar]
  144. Agrawal A, Prakash YS. 144.  2014. Obesity, metabolic syndrome, and airway disease: a bioenergetic problem?. Immunol. Allergy Clin. North Am. 34:4785–96 [Google Scholar]
  145. Sexton P, Metcalf P, Kolbe J. 145.  2014. Respiratory effects of insulin sensitisation with metformin: a prospective observational study. COPD 11:2133–42 [Google Scholar]
  146. Barbi J, Pardoll D, Pan F. 146.  2013. Metabolic control of the Treg/Th17 axis. Immunol. Rev. 252:152–77 [Google Scholar]
  147. Lam HC, Cloonan SM, Bhashyam AR, Haspel JA, Singh A. 147.  et al. 2013. Histone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction. J. Clin. Investig. 123:125212–30 [Google Scholar]
  148. Gibson GJ, Loddenkemper R, Lundbäck B, Sibille Y. 148.  2013. Respiratory health and disease in Europe: the new European Lung White Book. Eur. Respir. J. 42:3559–63 [Google Scholar]
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