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Mitochondrial electron transport chain, ROS generation and uncoupling (Review)

  • Authors:
    • Ru‑Zhou Zhao
    • Shuai Jiang
    • Lin Zhang
    • Zhi‑Bin Yu
  • View Affiliations / Copyright

    Affiliations: Department of Aerospace Physiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
    Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].
  • Pages: 3-15
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    Published online on: May 8, 2019
       https://doi.org/10.3892/ijmm.2019.4188
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Abstract

The mammalian mitochondrial electron transport chain (ETC) includes complexes I‑IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. The first part of this review briefly introduces the structure and function of complexes I‑IV and ATP synthase, including the specific electron transfer process in each complex. Some electrons are directly transferred to O2 to generate reactive oxygen species (ROS) in the ETC. The second part of this review discusses the sites of ROS generation in each ETC complex, including sites IF and IQ in complex I, site IIF in complex II and site IIIQo in complex III, and the physiological and pathological regulation of ROS. As signaling molecules, ROS play an important role in cell proliferation, hypoxia adaptation and cell fate determination, but excessive ROS can cause irreversible cell damage and even cell death. The occurrence and development of a number of diseases are closely related to ROS overproduction. Finally, proton leak and uncoupling proteins (UCPS) are discussed. Proton leak consists of basal proton leak and induced proton leak. Induced proton leak is precisely regulated and induced by UCPs. A total of five UCPs (UCP1‑5) have been identified in mammalian cells. UCP1 mainly plays a role in the maintenance of body temperature in a cold environment through non‑shivering thermogenesis. The core role of UCP2‑5 is to reduce oxidative stress under certain conditions, therefore exerting cytoprotective effects. All diseases involving oxidative stress are associated with UCPs.
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1 

Mitchell P: Coupling of phosphorylation to electron and hydrogen transfer by a chemiosmotic type of mechanism. Nature. 191:144–148. 1961. View Article : Google Scholar : PubMed/NCBI

2 

Guo R, Zong S, Wu M, Gu J and Yang M: Architecture of human mitochondrial respiratory megacomplex I2III2IV2. Cell. 170:1247–1257.e1212. 2017. View Article : Google Scholar

3 

Iwata S, Lee JW, Okada K, Lee JK, Iwata M, Rasmussen B, Link TA, Ramaswamy S and Jap BK: Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex. Science. 281:64–71. 1998. View Article : Google Scholar : PubMed/NCBI

4 

Sazanov LA and Hinchliffe P: Structure of the hydrophilic domain of respiratory complex I from thermus thermophilus. Science. 311:1430–1436. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Efremov RG and Sazanov LA: Structure of the membrane domain of respiratory complex I. Nature. 476:414–420. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Jones AJ, Blaza JN, Varghese F and Hirst J: Respiratory complex I in Bos taurus and paracoccus denitrificans pumps four protons across the membrane for every NADH Oxidized. J Biol Chem. 292:4987–4995. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J and Walker JE: Bovine complex I is a complex of 45 different subunits. J Biol Chem. 281:32724–32727. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Vinothkumar KR, Zhu J and Hirst J: Architecture of mammalian respiratory complex I. Nature. 515:80–84. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Ohnishi ST, Shinzawa-Itoh K, Ohta K, Yoshikawa S and Ohnishi T: New insights into the superoxide generation sites in bovine heart NADH-ubiquinone oxidoreductase (Complex I): The significance of protein-associated ubiquinone and the dynamic shifting of generation sites between semiflavin and semiquinone radicals. Biochim Biophys Acta. 1797:1901–1909. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Gai Z, Matsuno A, Kato K, Kato S, Khan MRI, Shimizu T, Yoshioka T, Kato Y, Kishimura H, Kanno G, et al: Crystal structure of the 3.8-MDa respiratory supermolecule hemocyanin at 3.0 A resolution. Structure. 23:2204–2212. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Hunte C, Zickermann V and Brandt U: Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science. 329:448–451. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Formosa LE, Dibley MG, Stroud DA and Ryan MT: Building a complex complex: Assembly of mitochondrial respiratory chain complex I. Semin Cell Dev Biol. 76:154–162. 2018. View Article : Google Scholar

13 

Berrisford JM and Sazanov LA: Structural basis for the mechanism of respiratory complex I. J Biol Chem. 284:29773–29783. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Tan P, Feng Z, Zhang L, Hou T and Li Y: The mechanism of proton translocation in respiratory complex I from molecular dynamics. J Recept Signal Transduct Res. 35:170–179. 2015. View Article : Google Scholar

15 

Wikstrom M and Hummer G: Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications. Proc Natl Acad Sci USA. 109:4431–4436. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Chance B and Williams GR: Respiratory enzymes in oxidative phosphorylation. IV. The respiratory chain. J Biol Chem. 217:429–438. 1955.PubMed/NCBI

17 

Stoner CD: Determination of the P/2e-stoichiometries at the individual coupling sites in mitochondrial oxidative phosphorylation. Evidence for maximum values of 1.0, 0.5, and 1.0 at sites 1, 2, and 3. J Biol Chem. 262:10445–10453. 1987.PubMed/NCBI

18 

Ohnishi T: Structural biology: Piston drives a proton pump. Nature. 465:428–429. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Cecchini G: Function and structure of complex II of the respiratory chain. Annu Rev Biochem. 72:77–109. 2003. View Article : Google Scholar : PubMed/NCBI

20 

Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M and Rao Z: Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 121:1043–1057. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Bezawork-Geleta A, Rohlena J, Dong L, Pacak K and Neuzil J: Mitochondrial complex II: At the crossroads. Trends Biochem Sci. 42:312–325. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Iverson TM: Catalytic mechanisms of complex II enzymes: A structural perspective. Biochim Biophys Acta. 1827:648–657. 2013. View Article : Google Scholar

23 

Schagger H, Link TA, Engel WD and von Jagow G: Isolation of the eleven protein subunits of the bc1 complex from beef heart. Methods Enzymol. 126:224–237. 1986. View Article : Google Scholar : PubMed/NCBI

24 

Yang XH and Trumpower BL: Purification of a three-subunit ubiquinol-cytochrome c oxidoreductase complex from paracoccus denitrificans. J Biol Chem. 261:12282–12289. 1986.PubMed/NCBI

25 

Gao X, Wen X, Esser L, Quinn B, Yu L, Yu CA and Xia D: Structural basis for the quinone reduction in the bc1 complex: A comparative analysis of crystal structures of mitochondrial cytochrome bc1 with bound substrate and inhibitors at the Qi site. Biochemistry. 42:9067–9080. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Mitchell P: Chemiosmotic coupling in energy transduction: A logical development of biochemical knowledge. J Bioenerg. 3:5–24. 1972. View Article : Google Scholar : PubMed/NCBI

27 

Mitchell P: Possible molecular mechanisms of the protonmotive function of cytochrome systems. J Theor Biol. 62:327–367. 1976. View Article : Google Scholar : PubMed/NCBI

28 

Trumpower BL: A concerted, alternating sites mechanism of ubiquinol oxidation by the dimeric cytochrome bc(1) complex. Biochim Biophys Acta. 1555:166–173. 2002. View Article : Google Scholar : PubMed/NCBI

29 

Kadenbach B and Hüttemann M: The subunit composition and function of mammalian cytochrome c oxidase. Mitochondrion. 24:64–76. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R and Yoshikawa S: The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A. Science. 272:1136–1144. 1996. View Article : Google Scholar : PubMed/NCBI

31 

Konstantinov AA: Cytochrome c oxidase: Intermediates of the catalytic cycle and their energy-coupled interconversion. FEBS Lett. 586:630–639. 2012. View Article : Google Scholar

32 

Sharma V and Wikstrom M: The role of the K-channel and the active-site tyrosine in the catalytic mechanism of cytochrome c oxidase. Biochim Biophys Acta. 1857:1111–1115. 2016. View Article : Google Scholar : PubMed/NCBI

33 

Varanasi L and Hosler JP: Subunit III-depleted cytochrome c oxidase provides insight into the process of proton uptake by proteins. Biochim Biophys Acta. 1817:545–551. 2012. View Article : Google Scholar :

34 

Alnajjar KS, Hosler J and Prochaska L: Role of the N-terminus of subunit III in proton uptake in cytochrome c oxidase of Rhodobacter sphaeroides. Biochemistry. 53:496–504. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Arnold S and Kadenbach B: Cell respiration is controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase. Eur J Biochem. 249:350–354. 1997. View Article : Google Scholar : PubMed/NCBI

36 

Arnold S and Kadenbach B: The intramitochondrial ATP/ADP-ratio controls cytochrome c oxidase activity allosteri-cally. FEBS Lett. 443:105–108. 1999. View Article : Google Scholar : PubMed/NCBI

37 

Arnold S, Goglia F and Kadenbach B: 3,5-Diiodothyronine binds to subunit Va of cytochrome-c oxidase and abolishes the allosteric inhibition of respiration by ATP. Eur J Biochem. 252:325–330. 1998. View Article : Google Scholar : PubMed/NCBI

38 

Follmann K, Arnold S, Ferguson-Miller S and Kadenbach B: Cytochrome c oxidase from eucaryotes but not from procaryotes is allosterically inhibited by ATP. Biochem Mol Biol Int. 45:1047–1055. 1998.PubMed/NCBI

39 

Shimada S, Shinzawa-Itoh K, Baba J, Aoe S, Shimada A, Yamashita E, Kang J, Tateno M, Yoshikawa S and Tsukihara T: Complex structure of cytochrome c-cytochrome c oxidase reveals a novel protein-protein interaction mode. EMBO J. 36:291–300. 2017. View Article : Google Scholar

40 

Wikstrom MK: Proton pump coupled to cytochrome c oxidase in mitochondria. Nature. 266:271–273. 1977. View Article : Google Scholar : PubMed/NCBI

41 

Jonckheere AI, Smeitink JA and Rodenburg RJ: Mitochondrial ATP synthase: Architecture, function and pathology. J Inherit Metab Dis. 35:211–225. 2012. View Article : Google Scholar :

42 

Dickson VK, Silvester JA, Fearnley IM, Leslie AG and Walker JE: On the structure of the stator of the mitochondrial ATP synthase. EMBO J. 25:2911–2918. 2006. View Article : Google Scholar : PubMed/NCBI

43 

Watt IN, Montgomery MG, Runswick MJ, Leslie AG and Walker JE: Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci USA. 107:16823–16827. 2010. View Article : Google Scholar : PubMed/NCBI

44 

Pecina P, Nůsková H, Karbanová V, Kaplanová V, Mráček T and Houštěk J: Role of the mitochondrial ATP synthase central stalk subunits γ and δ in the activity and assembly of the mammalian enzyme. Biochim Biophys Acta Bioenerg. 1859:374–381. 2018. View Article : Google Scholar : PubMed/NCBI

45 

Guo R, Gu J, Zong S, Wu M and Yang M: Structure and mechanism of mitochondrial electron transport chain. Biomed J. 41:9–20. 2018. View Article : Google Scholar : PubMed/NCBI

46 

Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M and Sazanov LA: Atomic structure of the entire mammalian mitochondrial complex I. Nature. 538:406–410. 2016. View Article : Google Scholar : PubMed/NCBI

47 

Hahn A, Parey K, Bublitz M, Mills DJ, Zickermann V, Vonck J, Kühlbrandt W and Meier T: Structure of a complete ATP synthase dimer reveals the molecular basis of inner mitochondrial membrane morphology. Mol Cell. 63:445–456. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Turrens JF: Mitochondrial formation of reactive oxygen species. J Physiol. 552:335–344. 2003. View Article : Google Scholar : PubMed/NCBI

49 

Cadenas E and Davies KJ: Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 29:222–230. 2000. View Article : Google Scholar : PubMed/NCBI

50 

Brand MD: Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med. 100:14–31. 2016. View Article : Google Scholar : PubMed/NCBI

51 

Kowaltowski AJ, de Souza-Pinto NC, Castilho RF and Vercesi AE: Mitochondria and reactive oxygen species. Free Radic Biol Med. 47:333–343. 2009. View Article : Google Scholar : PubMed/NCBI

52 

Brand MD: The sites and topology of mitochondrial superoxide production. Exp Gerontol. 45:466–472. 2010. View Article : Google Scholar : PubMed/NCBI

53 

Hernansanz-Agustin P, Ramos E, Navarro E, Parada E, Sánchez-López N, Peláez-Aguado L, Cabrera-García JD, Tello D, Buendia I, Marina A, et al: Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia. Redox Biol. 12:1040–1051. 2017. View Article : Google Scholar : PubMed/NCBI

54 

Hoekstra AS and Bayley JP: The role of complex II in disease. Biochim Biophys Acta. 1827:543–551. 2013. View Article : Google Scholar

55 

Cecchini G: Respiratory complex II: Role in cellular physiology and disease. Biochim Biophys Acta. 1827:541–542. 2013. View Article : Google Scholar : PubMed/NCBI

56 

Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA and Brand MD: Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. 287:27255–27264. 2012. View Article : Google Scholar : PubMed/NCBI

57 

Ackrell BA, Kearney EB and Singer TP: Mammalian succinate dehydrogenase. Methods Enzymol. 53:466–483. 1978. View Article : Google Scholar : PubMed/NCBI

58 

Turrens JF, Alexandre A and Lehninger AL: Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys. 237:408–414. 1985. View Article : Google Scholar : PubMed/NCBI

59 

Richter C, Gogvadze V, Laffranchi R, Schlapbach R, Schweizer M, Suter M, Walter P and Yaffee M: Oxidants in mitochondria: From physiology to diseases. Biochim Biophys Acta. 1271:67–74. 1995. View Article : Google Scholar : PubMed/NCBI

60 

Muller FL, Liu Y and Van Remmen H: Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 279:49064–49073. 2004. View Article : Google Scholar : PubMed/NCBI

61 

D'Autreaux B and Toledano MB: ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 8:813–824. 2007. View Article : Google Scholar : PubMed/NCBI

62 

Bedard K and Krause KH: The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev. 87:245–313. 2007. View Article : Google Scholar : PubMed/NCBI

63 

Treberg JR, Quinlan CL and Brand MD: Hydrogen peroxide efflux from muscle mitochondria underestimates matrix superoxide production-a correction using glutathione depletion. FEBS J. 277:2766–2778. 2010. View Article : Google Scholar : PubMed/NCBI

64 

Quinlan CL, Gerencser AA, Treberg JR and Brand MD: The mechanism of superoxide production by the antimycin-inhibited mitochondrial Q-cycle. J Biol Chem. 286:31361–31372. 2011. View Article : Google Scholar : PubMed/NCBI

65 

Erecinska M and Wilson DF: The effect of antimycin A on cytochromes b561, b566, and their relationship to ubiquinone and the iron-sulfer centers S-1 (+N-2) and S-3. Arch Biochem Biophys. 174:143–157. 1976. View Article : Google Scholar : PubMed/NCBI

66 

Orr AL, Vargas L, Turk CN, Baaten JE, Matzen JT, Dardov VJ, Attle SJ, Li J, Quackenbush DC, Goncalves RL, et al: Suppressors of superoxide production from mitochondrial complex III. Nat Chem Biol. 11:834–836. 2015. View Article : Google Scholar : PubMed/NCBI

67 

Muramoto K, Ohta K, Shinzawa-Itoh K, Kanda K, Taniguchi M, Nabekura H, Yamashita E, Tsukihara T and Yoshikawa S: Bovine cytochrome c oxidase structures enable O2 reduction with minimization of reactive oxygens and provide a proton-pumping gate. Proc Natl Acad Sci USA. 107:7740–7745. 2010. View Article : Google Scholar : PubMed/NCBI

68 

De Giusti VC, Caldiz CI, Ennis IL, Perez NG, Cingolani HE and Aiello EA: Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS). Front Physiol. 4:1262013. View Article : Google Scholar : PubMed/NCBI

69 

Diebold L and Chandel NS: Mitochondrial ROS regulation of proliferating cells. Free Radic Biol Med. 100:86–93. 2016. View Article : Google Scholar : PubMed/NCBI

70 

Kaminskyy VO and Zhivotovsky B: Free radicals in cross talk between autophagy and apoptosis. Antioxid Redox Signal. 21:86–102. 2014. View Article : Google Scholar

71 

Emerling BM, Weinberg F, Snyder C, Burgess Z, Mutlu GM, Viollet B, Budinger GR and Chandel NS: Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radic Biol Med. 46:1386–1391. 2009. View Article : Google Scholar : PubMed/NCBI

72 

Betzen C, White R, Zehendner CM, Pietrowski E, Bender B, Luhmann HJ and Kuhlmann CR: Oxidative stress upregulates the NMDA receptor on cerebrovascular endothelium. Free Radic Biol Med. 47:1212–1220. 2009. View Article : Google Scholar : PubMed/NCBI

73 

Huddleston AT, Tang W, Takeshima H, Hamilton SL and Klann E: Superoxide-induced potentiation in the hippocampus requires activation of ryanodine receptor type 3 and ERK. J Neurophysiol. 99:1565–1571. 2008. View Article : Google Scholar : PubMed/NCBI

74 

Hidalgo C and Arias-Cavieres A: Calcium, reactive oxygen species, and synaptic plasticity. Physiology (Bethesda). 31:201–215. 2016.

75 

Shetty PK, Huang FL and Huang KP: Ischemia-elicited oxidative modulation of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 283:5389–5401. 2008. View Article : Google Scholar : PubMed/NCBI

76 

Kemmerling U, Munoz P, Muller M, Sánchez G, Aylwin ML, Klann E, Carrasco MA and Hidalgo C: Calcium release by ryanodine receptors mediates hydrogen peroxide-induced activation of ERK and CREB phosphorylation in N2a cells and hippocampal neurons. Cell Calcium. 41:491–502. 2007. View Article : Google Scholar

77 

Massaad CA and Klann E: Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. 14:2013–2054. 2011. View Article : Google Scholar :

78 

Beckhauser TF, Francis-Oliveira J and De Pasquale R: Reactive oxygen species: Physiological and physiopathological effects on synaptic plasticity. J Exp Neurosci. 10(Suppl 1): S23–S48. 2016.

79 

Gasperini RJ, Pavez M, Thompson AC, Mitchell CB, Hardy H, Young KM, Chilton JK and Foa L: How does calcium interact with the cytoskeleton to regulate growth cone motility during axon pathfinding? Mol Cell Neurosci. 84:29–35. 2017. View Article : Google Scholar : PubMed/NCBI

80 

Oswald MCW, Garnham N, Sweeney ST and Landgraf M: Regulation of neuronal development and function by ROS. FEBS Lett. 592:679–691. 2018. View Article : Google Scholar : PubMed/NCBI

81 

Hongpaisan J, Winters CA and Andrews SB: Calcium-dependent mitochondrial superoxide modulates nuclear CREB phosphorylation in hippocampal neurons. Mol Cell Neurosci. 24:1103–1115. 2003. View Article : Google Scholar : PubMed/NCBI

82 

Orrenius S, Gogvadze V and Zhivotovsky B: Mitochondrial oxidative stress: Implications for cell death. Annu Rev Pharmacol Toxicol. 47:143–183. 2007. View Article : Google Scholar

83 

Cingolani HE, Perez NG, Aiello EA, Ennis IL, Garciarena CD, Villa-Abrille MC, Dulce RA, Caldiz CI, Yeves AM, Correa MV, et al: Early signals after stretch leading to cardiac hypertrophy. Key role of NHE-1. Front Biosci. 13:7096–7114. 2008. View Article : Google Scholar : PubMed/NCBI

84 

Palomeque J, Rueda OV, Sapia L, Valverde CA, Salas M, Petroff MV and Mattiazzi A: Angiotensin II-induced oxidative stress resets the Ca2+ dependence of Ca2+-calmodulin protein kinase II and promotes a death pathway conserved across different species. Circ Res. 105:1204–1212. 2009. View Article : Google Scholar : PubMed/NCBI

85 

Wang H and Patterson C: Roles of reactive oxygen species in physiology and pathology. John Wiley & Sons, Inc; Hoboken, NJ: pp. 379–392. 2015

86 

Robin E, Guzy RD, Loor G, Iwase H, Waypa GB, Marks JD, Hoek TL and Schumacker PT: Oxidant stress during simulated ischemia primes cardiomyocytes for cell death during reperfusion. J Biol Chem. 282:19133–19143. 2007. View Article : Google Scholar : PubMed/NCBI

87 

Wang L, Azad N, Kongkaneramit L, Chen F, Lu Y, Jiang BH and Rojanasakul Y: The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation. J Immunol. 180:3072–3080. 2008. View Article : Google Scholar : PubMed/NCBI

88 

Circu ML and Aw TY: Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med. 48:749–762. 2010. View Article : Google Scholar : PubMed/NCBI

89 

Deng Y, Ren X, Yang L, Lin Y and Wu X: A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell. 115:61–70. 2003. View Article : Google Scholar : PubMed/NCBI

90 

Hattori K, Naguro I, Runchel C and Ichijo H: The roles of ASK family proteins in stress responses and diseases. Cell Commun Signal. 7:92009. View Article : Google Scholar : PubMed/NCBI

91 

Sinha K, Das J, Pal PB and Sil PC: Oxidative stress: The mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 87:1157–1180. 2013. View Article : Google Scholar : PubMed/NCBI

92 

Shen C, Cai GQ, Peng JP and Chen XD: Autophagy protects chondrocytes from glucocorticoids-induced apoptosis via ROS/Akt/FOXO3 signaling. Osteoarthritis Cartilage. 23:2279–2287. 2015. View Article : Google Scholar : PubMed/NCBI

93 

Shah SZA, Zhao D, Hussain T, Sabir N, Mangi MH and Yang L: p62-Keap1-NRF2-ARE pathway: A contentious player for selective targeting of autophagy, oxidative stress and mitochondrial dysfunction in prion diseases. Front Mol Neurosci. 11:3102018. View Article : Google Scholar : PubMed/NCBI

94 

Wu H, Huang S, Chen Z, Liu W, Zhou X and Zhang D: Hypoxia-induced autophagy contributes to the invasion of salivary adenoid cystic carcinoma through the HIF-1α/BNIP3 signaling pathway. Mol Med Rep. 12:6467–6474. 2015. View Article : Google Scholar : PubMed/NCBI

95 

Bensaad K, Cheung EC and Vousden KH: Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J. 28:3015–3026. 2009. View Article : Google Scholar : PubMed/NCBI

96 

Gurusamy N and Das DK: Autophagy, redox signaling, and ventricular remodeling. Antioxid Redox Signal. 11:1975–1988. 2009. View Article : Google Scholar : PubMed/NCBI

97 

Li R, Zhou P, Guo Y, Lee JS and Zhou B: Tris (1, 3-dichloro-2-propyl) phosphate induces apoptosis and autophagy in SH-SY5Y cells: Involvement of ROS-mediated AMPK/mTOR/ULK1 pathways. Food Chem Toxicol. 100:183–196. 2017. View Article : Google Scholar

98 

Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H and Vandenabeele P: Regulated necrosis: The expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 15:135–147. 2014. View Article : Google Scholar : PubMed/NCBI

99 

Schenk B and Fulda S: Reactive oxygen species regulate Smac mimetic/TNFα-induced necroptotic signaling and cell death. Oncogene. 34:5796–5806. 2015. View Article : Google Scholar : PubMed/NCBI

100 

Morgan MJ and Liu ZG: Reactive oxygen species in TNFalpha-induced signaling and cell death. Mol Cells. 30:1–12. 2010. View Article : Google Scholar : PubMed/NCBI

101 

Ying Y, Kim J, Westphal SN, Long KE and Padanilam BJ: Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury. J Am Soc Nephrol. 25:2707–2716. 2014. View Article : Google Scholar : PubMed/NCBI

102 

Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC and Salter RD: Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J Immunol. 191:5230–5238. 2013. View Article : Google Scholar : PubMed/NCBI

103 

Zhou R, Tardivel A, Thorens B, Choi I and Tschopp J: Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 11:136–140. 2010. View Article : Google Scholar

104 

Scholl FA, Dumesic PA, Barragan DI, Harada K, Bissonauth V, Charron J and Khavari PA: Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and raf-induced hyperplasia. Dev Cell. 12:615–629. 2007. View Article : Google Scholar : PubMed/NCBI

105 

Hulsmans M, Van Dooren E and Holvoet P: Mitochondrial reactive oxygen species and risk of atherosclerosis. Curr Atheroscler Rep. 14:264–276. 2012. View Article : Google Scholar : PubMed/NCBI

106 

Kattoor AJ, Pothineni NVK, Palagiri D and Mehta JL: Oxidative stress in atherosclerosis. Curr Atheroscler Rep. 19:422017. View Article : Google Scholar : PubMed/NCBI

107 

Montezano AC, Dulak-Lis M, Tsiropoulou S, Harvey A, Briones AM and Touyz RM: Oxidative stress and human hypertension: Vascular mechanisms, biomarkers, and novel therapies. Can J Cardiol. 31:631–641. 2015. View Article : Google Scholar : PubMed/NCBI

108 

Sanderson TH, Reynolds CA, Kumar R, Przyklenk K and Huttemann M: Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol. 47:9–23. 2013. View Article : Google Scholar :

109 

Chouchani ET, Pell VR, James AM, Work LM, Saeb-Parsy K, Frezza C, Krieg T and Murphy MP: A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab. 23:254–263. 2016. View Article : Google Scholar : PubMed/NCBI

110 

Lorenzo O, Ramirez E, Picatoste B, Egido J and Tunon J: Alteration of energy substrates and ROS production in diabetic cardiomyopathy. Mediators Inflamm. 2013:4619672013. View Article : Google Scholar : PubMed/NCBI

111 

Zhao MX, Zhou B, Ling L, Xiong XQ, Zhang F, Chen Q, Li YH, Kang YM and Zhu GQ: Salusin-beta contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death Dis. 8:e26902017. View Article : Google Scholar

112 

Jaitovich A and Jourd'Heuil D: A brief overview of nitric oxide and reactive oxygen species signaling in hypoxia-induced pulmonary hypertension. Adv Exp Med Biol. 967:71–81. 2017. View Article : Google Scholar : PubMed/NCBI

113 

Fulton DJR, Li X, Bordan Z, Haigh S, Bentley A, Chen F and Barman SA: Reactive oxygen and nitrogen species in the development of pulmonary hypertension. Antioxidants (Basel). 6:E542017. View Article : Google Scholar

114 

Allaire J, Maltais F, LeBlanc P, Simard PM, Whittom F, Doyon JF, Simard C and Jobin J: Lipofuscin accumulation in the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Muscle Nerve. 25:383–389. 2002. View Article : Google Scholar : PubMed/NCBI

115 

Dekhuijzen PN, Aben KK, Dekker I, Aarts LP, Wielders PL, van Herwaarden CL and Bast A: Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 154:813–816. 1996. View Article : Google Scholar : PubMed/NCBI

116 

Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA and Barnes PJ: Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med. 162:1175–1177. 2000. View Article : Google Scholar : PubMed/NCBI

117 

Sabharwal SS and Schumacker PT: Mitochondrial ROS in cancer: Initiators, amplifiers or an achilles' heel? Nat Rev Cancer. 14:709–721. 2014. View Article : Google Scholar : PubMed/NCBI

118 

Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H and Lleonart ME: Oxidative stress and cancer: An overview. Ageing Res Rev. 12:376–390. 2013. View Article : Google Scholar

119 

Ahmad W, Ijaz B, Shabbiri K, Ahmed F and Rehman S: Oxidative toxicity in diabetes and Alzheimer's disease: Mechanisms behind ROS/RNS generation. J Biomed Sci. 24:762017. View Article : Google Scholar

120 

Rehman K and Akash MSH: Mechanism of generation of oxidative stress and pathophysiology of type 2 diabetes mellitus: How are they interlinked? J Cell Biochem. 118:3577–3585. 2017. View Article : Google Scholar : PubMed/NCBI

121 

Spahis S, Delvin E, Borys JM and Levy E: Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis. Antioxid Redox Signal. 26:519–541. 2017. View Article : Google Scholar

122 

Rolo AP, Teodoro JS and Palmeira CM: Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med. 52:59–69. 2012. View Article : Google Scholar

123 

de la Monte SM and Wands JR: Molecular indices of oxidative stress and mitochondrial dysfunction occur early and oftenprogresswith severity of Alzheimer's disease. J Alzheimers Dis. 9:167–181. 2006. View Article : Google Scholar : PubMed/NCBI

124 

Dias V, Junn E and Mouradian MM: The role of oxidative stress in Parkinson's disease. J Parkinsons Dis. 3:461–491. 2013.PubMed/NCBI

125 

Nagano T, Mizuno M, Morita K and Nawa H: Pathological implications of oxidative stress in patients and animal models with schizophrenia: The role of epidermal growth factor receptor signaling. Curr Top Behav Neurosci. 29:429–446. 2016. View Article : Google Scholar

126 

Mahadik SP, Pillai A, Joshi S and Foster A: Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia. Int Rev Psychiatry. 18:119–131. 2006. View Article : Google Scholar : PubMed/NCBI

127 

Kwon DN, Park WJ, Choi YJ, Gurunathan S and Kim JH: Oxidative stress and ROS metabolism via down-regulation of sirtuin 3 expression in Cmahnull mice affect hearing loss. Aging (Albany NY). 7:579–594. 2015. View Article : Google Scholar

128 

Kamogashira T, Fujimoto C and Yamasoba T: Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss. Biomed Res Int. 2015:6172072015. View Article : Google Scholar : PubMed/NCBI

129 

Marazita MC, Dugour A, Marquioni-Ramella MD, Figueroa JM and Suburo AM: Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for age-related macular degeneration. Redox Biol. 7:78–87. 2016. View Article : Google Scholar :

130 

Nita M and Grzybowski A: The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid Med Cell Longev. 2016:31647342016. View Article : Google Scholar : PubMed/NCBI

131 

Ghosh S, Sulistyoningrum DC, Glier MB, Verchere CB and Devlin AM: Altered glutathione homeostasis in heart augments cardiac lipotoxicity associated with diet-induced obesity in mice. J Biol Chem. 286:42483–42493. 2011. View Article : Google Scholar : PubMed/NCBI

132 

Mandas A, Iorio EL, Congiu MG, Balestrieri C, Mereu A, Cau D, Dessì S and Curreli N: Oxidative imbalance in HIV-1 infected patients treated with antiretroviral therapy. J Biomed Biotechnol. 2009:7495752009. View Article : Google Scholar : PubMed/NCBI

133 

Shin DH, Martinez SS, Parsons M, Jayaweera DT, Campa A and Baum MK: Relationship of oxidative stress with HIV disease progression in HIV/HCV Co-infected and HIV mono-infected adults in miami. Int J Biosci Biochem Bioinforma. 2:217–223. 2012.PubMed/NCBI

134 

Haycock JW, MacNeil S, Jones P, Harris JB and Mantle D: Oxidative damage to muscle protein in Duchenne muscular dystrophy. Neuroreport. 8:357–361. 1996. View Article : Google Scholar : PubMed/NCBI

135 

Austin L, de Niese M, McGregor A, Arthur H, Gurusinghe A and Gould MK: Potential oxyradical damage and energy status in individual muscle fibres from degenerating muscle diseases. Neuromuscul Disord. 2:27–33. 1992. View Article : Google Scholar : PubMed/NCBI

136 

Lee G, Kim HJ and Kim HM: RhoA-JNK regulates the E-cadherin junctions of human gingival epithelial cells. J Dent Res. 95:284–291. 2016. View Article : Google Scholar

137 

Nobes CD, Brown GC, Olive PN and Brand MD: Nonohmic proton conductance of the mitochondrial inner membrane in hepatocytes. J Biol Chem. 265:12903–12909. 1990.PubMed/NCBI

138 

Brand MD, Turner N, Ocloo A, Else PL and Hulbert AJ: Proton conductance and fatty acyl composition of liver mitochondria correlates with body mass in birds. Biochem J. 376:741–748. 2003. View Article : Google Scholar : PubMed/NCBI

139 

Porter RK and Brand MD: Body mass dependence of H+ leak in mitochondria and its relevance to metabolic rate. Nature. 362:628–630. 1993. View Article : Google Scholar : PubMed/NCBI

140 

Brookes PS, Rolfe DF and Brand MD: The proton permeability of liposomes made from mitochondrial inner membrane phospholipids: Comparison with isolated mitochondria. J Membr Biol. 155:167–174. 1997. View Article : Google Scholar : PubMed/NCBI

141 

Brand MD, Pakay JL, Ocloo A, Kokoszka J, Wallace DC, Brookes PS and Cornwall EJ: The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J. 392:353–362. 2005. View Article : Google Scholar : PubMed/NCBI

142 

Parker N, Crichton PG, Vidal-Puig AJ and Brand MD: Uncoupling protein-1 (UCP1) contributes to the basal proton conductance of brown adipose tissue mitochondria. J Bioenerg Biomembr. 41:335–342. 2009. View Article : Google Scholar : PubMed/NCBI

143 

Shabalina IG, Ost M, Petrovic N, Vrbacky M, Nedergaard J and Cannon B: Uncoupling protein-1 is not leaky. Biochim Biophys Acta. 1797:773–784. 2010. View Article : Google Scholar : PubMed/NCBI

144 

Roussel D, Harding M, Runswick MJ, Walker JE and Brand MD: Does any yeast mitochondrial carrier have a native uncoupling protein function? J Bioenerg Biomembr. 34:165–176. 2002. View Article : Google Scholar : PubMed/NCBI

145 

Krauss S, Zhang CY and Lowell BB: The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol. 6:248–261. 2005. View Article : Google Scholar : PubMed/NCBI

146 

Huang SG and Klingenberg M: Fluorescent nucleotide derivatives as specific probes for the uncoupling protein: Thermodynamics and kinetics of binding and the control by pH. Biochemistry. 34:349–360. 1995. View Article : Google Scholar : PubMed/NCBI

147 

Xia C, Liu JZ and Xu Y: Effects of GDP on the activity and expression of mitochondrial uncoupling proteins in rat brain in vitro. Sheng Li Xue Bao. 60:492–496. 2008.In Chinese. PubMed/NCBI

148 

Ramsden DB, Ho PW, Ho JW, Liu HF, So DH, Tse HM, Chan KH and Ho SL: Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): Structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction. Brain Behav. 2:468–478. 2012. View Article : Google Scholar : PubMed/NCBI

149 

Hoang T, Smith MD and Jelokhani-Niaraki M: Toward understanding the mechanism of ion transport activity of neuronal uncoupling proteins UCP2, UCP4, and UCP5. Biochemistry. 51:4004–4014. 2012. View Article : Google Scholar : PubMed/NCBI

150 

Andrews ZB, Diano S and Horvath TL: Mitochondrial uncoupling proteins in the cns: In support of function and survival. Nat Rev Neurosci. 6:829–840. 2005. View Article : Google Scholar : PubMed/NCBI

151 

Nicholls DG and Locke RM: Thermogenic mechanisms in brown fat. Physiol Rev. 64:1–64. 1984. View Article : Google Scholar : PubMed/NCBI

152 

Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B and Nedergaard J: UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 5:1196–1203. 2013. View Article : Google Scholar : PubMed/NCBI

153 

Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B and Nedergaard J: Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J. 15:2048–2050. 2001. View Article : Google Scholar : PubMed/NCBI

154 

Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME and Kozak LP: Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 387:90–94. 1997. View Article : Google Scholar : PubMed/NCBI

155 

Divakaruni AS and Brand MD: The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda). 26:192–205. 2011.

156 

Granneman JG, Burnazi M, Zhu Z and Schwamb LA: White adipose tissue contributes to UCP1-independent thermogenesis. Am J Physiol Endocrinol Metab. 285:E1230–E1236. 2003. View Article : Google Scholar : PubMed/NCBI

157 

Adams AE, Kelly OM and Porter RK: Absence of mitochondrial uncoupling protein 1 affects apoptosis in thymocytes, thymocyte/T-cell profile and peripheral T-cell number. Biochim Biophys Acta. 1797:807–816. 2010. View Article : Google Scholar : PubMed/NCBI

158 

Adams AE, Hanrahan O, Nolan DN, Voorheis HP, Fallon P and Porter RK: Images of mitochondrial UCP 1 in mouse thymocytes using confocal microscopy. Biochim Biophys Acta. 1777:115–117. 2008. View Article : Google Scholar

159 

Adams AE, Carroll AM, Fallon PG and Porter RK: Mitochondrial uncoupling protein 1 expression in thymocytes. Biochim Biophys Acta. 1777:772–776. 2008. View Article : Google Scholar : PubMed/NCBI

160 

Sale MM, Hsu FC, Palmer ND, Gordon CJ, Keene KL, Borgerink HM, Sharma AJ, Bergman RN, Taylor KD, Saad MF and Norris JM: The uncoupling protein 1 gene, UCP1, is expressed in mammalian islet cells and associated with acute insulin response to glucose in african american families from the IRAS family study. BMC Endocr Disord. 7:12007. View Article : Google Scholar : PubMed/NCBI

161 

Shabalina IG, Jacobsson A, Cannon B and Nedergaard J: Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem. 279:38236–38248. 2004. View Article : Google Scholar : PubMed/NCBI

162 

Breen EP, Gouin SG, Murphy AF, Haines LR, Jackson AM, Pearson TW, Murphy PV and Porter RK: On the mechanism of mitochondrial uncoupling protein 1 function. J Biol Chem. 281:2114–2119. 2006. View Article : Google Scholar

163 

Rial E, Aguirregoitia E, Jimenez-Jimenez J and Ledesma A: Alkylsulfonates activate the uncoupling protein UCP1: Implications for the transport mechanism. Biochim Biophys Acta. 1608:122–130. 2004. View Article : Google Scholar : PubMed/NCBI

164 

Klingenberg M and Huang SG: Structure and function of the uncoupling protein from brown adipose tissue. Biochim Biophys Acta. 1415:271–296. 1999. View Article : Google Scholar : PubMed/NCBI

165 

Garlid KD, Jaburek M and Jezek P: The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett. 438:10–14. 1998. View Article : Google Scholar : PubMed/NCBI

166 

Garlid KD, Orosz DE, Modriansky M, Vassanelli S and Jezek P: On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem. 271:2615–2620. 1996. View Article : Google Scholar : PubMed/NCBI

167 

Winkler E and Klingenberg M: Effect of fatty acids on H+ transport activity of the reconstituted uncoupling protein. J Biol Chem. 269:2508–2515. 1994.PubMed/NCBI

168 

Skulachev VP: Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett. 294:158–162. 1991. View Article : Google Scholar : PubMed/NCBI

169 

Klingenberg M and Winkler E: The reconstituted isolated uncoupling protein is a membrane potential driven H+ translocator. EMBO J. 4:3087–3092. 1985. View Article : Google Scholar : PubMed/NCBI

170 

Azzu V and Brand MD: The on-off switches of the mitochondrial uncoupling proteins. Trends Biochem Sci. 35:298–307. 2010. View Article : Google Scholar

171 

Ricquier D and Bouillaud F: The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J. 345(Pt 2): 161–179. 2000. View Article : Google Scholar : PubMed/NCBI

172 

Friederich M, Fasching A, Hansell P, Nordquist L and Palm F: Diabetes-induced up-regulation of uncoupling protein-2 results in increased mitochondrial uncoupling in kidney proximal tubular cells. Biochim Biophys Acta. 1777:935–940. 2008. View Article : Google Scholar : PubMed/NCBI

173 

Flachs P, Sponarova J, Kopecky P, Horvath O, Sediva A, Nibbelink M, Casteilla L, Medrikova D, Neckar J, Kolar F and Kopecky J: Mitochondrial uncoupling protein 2 gene transcript levels are elevated in maturating erythroid cells. FEBS Lett. 581:1093–1097. 2007. View Article : Google Scholar : PubMed/NCBI

174 

Affourtit C and Brand MD: On the role of uncoupling protein-2 in pancreatic beta cells. Biochim Biophys Acta. 1777:973–979. 2008. View Article : Google Scholar : PubMed/NCBI

175 

Cadenas S: Mitochondrial uncoupling, ROS generation and cardioprotection. Biochim Biophys Acta Bioenerg. 1859:940–950. 2018. View Article : Google Scholar : PubMed/NCBI

176 

Teshima Y, Akao M, Jones SP and Marban E: Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circ Res. 93:192–200. 2003. View Article : Google Scholar : PubMed/NCBI

177 

Vidal-Puig A, Solanes G, Grujic D, Flier JS and Lowell BB: UCP3: An uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun. 235:79–82. 1997. View Article : Google Scholar : PubMed/NCBI

178 

Aguirre E and Cadenas S: GDP and carboxyatractylate inhibit 4-hydroxynonenal-activated proton conductance to differing degrees in mitochondria from skeletal muscle and heart. Biochim Biophys Acta. 1797:1716–1726. 2010. View Article : Google Scholar : PubMed/NCBI

179 

Kelly OM and Porter RK: Absence of mitochondrial uncoupling protein 3: Effect on thymus and spleen in the fed and fasted mice. Biochim Biophys Acta. 1807:1064–1074. 2011. View Article : Google Scholar : PubMed/NCBI

180 

Mori S, Yoshizuka N, Takizawa M, Takema Y, Murase T, Tokimitsu I and Saito M: Expression of uncoupling proteins in human skin and skin-derived cells. J Invest Dermatol. 128:1894–1900. 2008. View Article : Google Scholar

181 

Harper ME and Himms-Hagen J: Mitochondrial efficiency: Lessons learned from transgenic mice. Biochim Biophys Acta. 1504:159–172. 2001. View Article : Google Scholar : PubMed/NCBI

182 

Negre-Salvayre A, Hirtz C, Carrera G, Cazenave R, Troly M, Salvayre R, Pénicaud L and Casteilla L: A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 11:809–815. 1997. View Article : Google Scholar : PubMed/NCBI

183 

Suski JM, Lebiedzinska M, Bonora M, Pinton P, Duszynski J and Wieckowski MR: Relation between mitochondrial membrane potential and ROS formation. Methods Mol Biol. 810:183–205. 2012. View Article : Google Scholar

184 

Pi J, Bai Y, Daniel KW, Liu D, Lyght O, Edelstein D, Brownlee M, Corkey BE and Collins S: Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic beta-cell function. Endocrinology. 150:3040–3048. 2009. View Article : Google Scholar : PubMed/NCBI

185 

Vidal-Puig AJ, Grujic D, Zhang CY, Hagen T, Boss O, Ido Y, Szczepanik A, Wade J, Mootha V, Cortright R, et al: Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem. 275:16258–16266. 2000. View Article : Google Scholar : PubMed/NCBI

186 

Brand MD, Pamplona R, Portero-Otin M, Requena JR, Roebuck SJ, Buckingham JA, Clapham JC and Cadenas S: Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3. Biochem J. 368:597–603. 2002. View Article : Google Scholar : PubMed/NCBI

187 

Brand MD: Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol. 35:811–820. 2000. View Article : Google Scholar : PubMed/NCBI

188 

Dlaskova A, Clarke KJ and Porter RK: The role of UCP 1 in production of reactive oxygen species by mitochondria isolated from brown adipose tissue. Biochim Biophys Acta. 1797:1470–1476. 2010. View Article : Google Scholar : PubMed/NCBI

189 

Shabalina IG, Vrbacky M, Pecinova A, Kalinovich AV, Drahota Z, Houštěk J, Mráček T, Cannon B and Nedergaard J: ROS production in brown adipose tissue mitochondria: The question of UCP1-dependence. Biochim Biophys Acta. 1837:2017–2030. 2014. View Article : Google Scholar : PubMed/NCBI

190 

Skulachev VP: Anion carriers in fatty acid-mediated physiological uncoupling. J Bioenerg Biomembr. 31:431–445. 1999. View Article : Google Scholar

191 

Schrauwen P and Hesselink MK: The role of uncoupling protein 3 in fatty acid metabolism: Protection against lipotoxicity? Proc Nutr Soc. 63:287–292. 2004. View Article : Google Scholar : PubMed/NCBI

192 

Bouillaud F, Couplan E, Pecqueur C and Ricquier D: Homologues of the uncoupling protein from brown adipose tissue (UCP1): UCP2, UCP3, BMCP1 and UCP4. Biochim Biophys Acta. 1504:107–119. 2001. View Article : Google Scholar : PubMed/NCBI

193 

Mao W, Yu XX, Zhong A, Li W, Brush J, Sherwood SW, Adams SH and Pan G: UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Lett. 443:326–330. 1999. View Article : Google Scholar : PubMed/NCBI

194 

Sanchis D, Fleury C, Chomiki N, Goubern M, Huang Q, Neverova M, Grégoire F, Easlick J, Raimbault S, Lévi-Meyrueis C, et al: BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem. 273:34611–34615. 1998. View Article : Google Scholar : PubMed/NCBI

195 

Zhang M, Wang B, Ni YH, Liu F, Fei L, Pan XQ, Guo M, Chen RH and Guo XR: Overexpression of uncoupling protein 4 promotes proliferation and inhibits apoptosis and differentiation of preadipocytes. Life Sci. 79:1428–1435. 2006. View Article : Google Scholar : PubMed/NCBI

196 

Slocinska M, Barylski J and Jarmuszkiewicz W: Uncoupling proteins of invertebrates: A review. IUBMB Life. 68:691–699. 2016. View Article : Google Scholar : PubMed/NCBI

197 

Ivanova MV, Hoang T, McSorley FR, Krnac G, Smith MD and Jelokhani-Niaraki M: A comparative study on conformation and ligand binding of the neuronal uncoupling proteins. Biochemistry. 49:512–521. 2010. View Article : Google Scholar

198 

Kwok KH, Ho PW, Chu AC, Ho JW, Liu HF, Yiu DC, Chan KH, Kung MH, Ramsden DB and Ho SL: Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic Biol Med. 49:1023–1035. 2010. View Article : Google Scholar : PubMed/NCBI

199 

Emerit J, Edeas M and Bricaire F: Neurodegenerative diseases and oxidative stress. Biomed Pharmacother. 58:39–46. 2004. View Article : Google Scholar : PubMed/NCBI

200 

Kim-Han JS and Dugan LL: Mitochondrial uncoupling proteins in the central nervous system. Antioxid Redox Signal. 7:1173–1181. 2005. View Article : Google Scholar : PubMed/NCBI

201 

Ho PW, Ho JW, Tse HM, So DH, Yiu DC, Liu HF, Chan KH, Kung MH, Ramsden DB and Ho SL: Uncoupling protein-4 (UCP4) increases ATP supply by interacting with mitochondrial complex II in neuroblastoma cells. PLoS One. 7:e328102012. View Article : Google Scholar : PubMed/NCBI

202 

Pfeiffer M, Kayzer EB, Yang X, Abramson E, Kenaston MA, Lago CU, Lo HH, Sedensky MM, Lunceford A, Clarke CF, et al: Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem. 286:37712–37720. 2011. View Article : Google Scholar : PubMed/NCBI

203 

Chan SL, Liu D, Kyriazis GA, Bagsiyao P, Ouyang X and Mattson MP: Mitochondrial uncoupling protein-4 regulates calcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem. 281:37391–37403. 2006. View Article : Google Scholar : PubMed/NCBI

204 

Walder K, Norman RA, Hanson RL, Schrauwen P, Neverova M, Jenkinson CP, Easlick J, Warden CH, Pecqueur C, Raimbault S, et al: Association between uncoupling protein polymorphisms (UCP2UCP3) and energy metabolism/obesity in pima indians. Hum Mol Genet. 7:1431–1435. 1998. View Article : Google Scholar : PubMed/NCBI

205 

Pheiffer C, Jacobs C, Patel O, Ghoor S, Muller C and Louw J: Expression of UCP2 in wistar rats varies according to age and the severity of obesity. J Physiol Biochem. 72:25–32. 2016. View Article : Google Scholar

206 

Millet L, Vidal H, Andreelli F, Larrouy D, Riou JP, Ricquier D, Laville M and Langin D: Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. J Clin Invest. 100:2665–2670. 1997. View Article : Google Scholar

207 

Robson-Doucette CA, Sultan S, Allister EM, Wikstrom JD, Koshkin V, Bhattacharjee A, Prentice KJ, Sereda SB, Shirihai OS and Wheeler MB: Beta-cell uncoupling protein 2 regulates reactive oxygen species production, which influences both insulin and glucagon secretion. Diabetes. 60:2710–2719. 2011. View Article : Google Scholar : PubMed/NCBI

208 

Gonzalez-Barroso MM, Giurgea I, Bouillaud F, Anedda A, Bellanné-Chantelot C, Hubert L, de Keyzer Y, de Lonlay P and Ricquier D: Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLoS One. 3:e38502008. View Article : Google Scholar : PubMed/NCBI

209 

Lameloise N, Muzzin P, Prentki M and Assimacopoulos-Jeannet F: Uncoupling protein 2: A possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes. 50:803–809. 2001. View Article : Google Scholar : PubMed/NCBI

210 

Patane G, Anello M, Piro S, Vigneri R, Purrello F and Rabuazzo AM: Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor-gamma inhibition. Diabetes. 51:2749–2756. 2002. View Article : Google Scholar : PubMed/NCBI

211 

Li W, Nichols K, Nathan CA and Zhao Y: Mitochondrial uncoupling protein 2 is up-regulated in human head and neck, skin, pancreatic, and prostate tumors. Cancer Biomark. 13:377–383. 2013. View Article : Google Scholar

212 

Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR and Baffy G: The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res. 68:2813–2819. 2008. View Article : Google Scholar : PubMed/NCBI

213 

Pons DG, Nadal-Serrano M, Torrens-Mas M, Valle A, Oliver J and Roca P: UCP2 inhibition sensitizes breast cancer cells to therapeutic agents by increasing oxidative stress. Free Radic Biol Med. 86:67–77. 2015. View Article : Google Scholar : PubMed/NCBI

214 

Kawanishi M, Fukuda T, Shimomura M, Inoue Y, Wada T, Tasaka R, Yasui T and Sumi T: Expression of UCP2 is associated with sensitivity to platinum-based chemotherapy for ovarian serous carcinoma. Oncol Lett. 15:9923–9928. 2018.PubMed/NCBI

215 

Franssen FM, Wouters EF, Baarends EM, Akkermans MA and Schols AM: Arm mechanical efficiency and arm exercise capacity are relatively preserved in chronic obstructive pulmonary disease. Med Sci Sports Exerc. 34:1570–1576. 2002. View Article : Google Scholar : PubMed/NCBI

216 

Gosker HR, Schrauwen P, Broekhuizen R, Hesselink MK, Moonen-Kornips E, Ward KA, Franssen FM, Wouters EF and Schols AM: Exercise training restores uncoupling protein-3 content in limb muscles of patients with chronic obstructive pulmonary disease. Am J Physiol. Endocrinol Metab. 290:E976–E981. 2006.

217 

Patti ME and Corvera S: The role of mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev. 31:364–395. 2010. View Article : Google Scholar : PubMed/NCBI

218 

Schrauwen P, Hesselink MK, Blaak EE, Borghouts LB, Schaart G, Saris WH and Keizer HA: Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes. 50:2870–2873. 2001. View Article : Google Scholar : PubMed/NCBI

219 

Yasuno K, Ando S, Misumi S, Makino S, Kulski JK, Muratake T, Kaneko N, Amagane H, Someya T, Inoko H, et al: Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 144B:250–253. 2007. View Article : Google Scholar

220 

Gigante AD, Andreazza AC, Lafer B, Yatham LN, Beasley CL and Young LT: Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia. Neurosci Lett. 505:47–51. 2011. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhao RZ, Jiang S, Zhang L and Yu ZB: Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int J Mol Med 44: 3-15, 2019.
APA
Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). Mitochondrial electron transport chain, ROS generation and uncoupling (Review). International Journal of Molecular Medicine, 44, 3-15. https://doi.org/10.3892/ijmm.2019.4188
MLA
Zhao, R., Jiang, S., Zhang, L., Yu, Z."Mitochondrial electron transport chain, ROS generation and uncoupling (Review)". International Journal of Molecular Medicine 44.1 (2019): 3-15.
Chicago
Zhao, R., Jiang, S., Zhang, L., Yu, Z."Mitochondrial electron transport chain, ROS generation and uncoupling (Review)". International Journal of Molecular Medicine 44, no. 1 (2019): 3-15. https://doi.org/10.3892/ijmm.2019.4188
Copy and paste a formatted citation
x
Spandidos Publications style
Zhao RZ, Jiang S, Zhang L and Yu ZB: Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int J Mol Med 44: 3-15, 2019.
APA
Zhao, R., Jiang, S., Zhang, L., & Yu, Z. (2019). Mitochondrial electron transport chain, ROS generation and uncoupling (Review). International Journal of Molecular Medicine, 44, 3-15. https://doi.org/10.3892/ijmm.2019.4188
MLA
Zhao, R., Jiang, S., Zhang, L., Yu, Z."Mitochondrial electron transport chain, ROS generation and uncoupling (Review)". International Journal of Molecular Medicine 44.1 (2019): 3-15.
Chicago
Zhao, R., Jiang, S., Zhang, L., Yu, Z."Mitochondrial electron transport chain, ROS generation and uncoupling (Review)". International Journal of Molecular Medicine 44, no. 1 (2019): 3-15. https://doi.org/10.3892/ijmm.2019.4188
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