1932

Abstract

Mitochondria of all tissues convert various metabolic substrates into two forms of energy: ATP and heat. Historically, the primary focus of research in mitochondrial bioenergetics was on the mechanisms of ATP production, while mitochondrial thermogenesis received significantly less attention. Nevertheless, mitochondrial heat production is crucial for the maintenance of body temperature, regulation of the pace of metabolism, and prevention of oxidative damage to mitochondria and the cell. In addition, mitochondrial thermogenesis has gained significance as a pharmacological target for treating metabolic disorders. Mitochondria produce heat as the result of H+ leak across their inner membrane. This review provides a critical assessment of the current field of mitochondrial H+ leak and thermogenesis, with a focus on the molecular mechanisms involved in the function and regulation of uncoupling protein 1 and the ADP/ATP carrier, the two proteins that mediate mitochondrial H+ leak.

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2022-02-10
2024-03-29
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Literature Cited

  1. 1. 
    Cannon B, Nedergaard J. 2004. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84:277–359
    [Google Scholar]
  2. 2. 
    Nicholls DG. 2017. The hunt for the molecular mechanism of brown fat thermogenesis. Biochimie 134:9–18
    [Google Scholar]
  3. 3. 
    Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. 2010. Mitochondrial proton and electron leaks. Essays Biochem 47:53–67
    [Google Scholar]
  4. 4. 
    Bernardi P. 1999. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79:1127–55
    [Google Scholar]
  5. 5. 
    Azzu V, Brand MD. 2010. The on-off switches of the mitochondrial uncoupling proteins. Trends Biochem. Sci. 35:298–307
    [Google Scholar]
  6. 6. 
    Aquila H, Link TA, Klingenberg M. 1985. The uncoupling protein from brown fat mitochondria is related to the mitochondrial ADP/ATP carrier. Analysis of sequence homologies and of folding of the protein in the membrane. EMBO J 4:2369–76
    [Google Scholar]
  7. 7. 
    Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H et al. 1997. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387:90–94
    [Google Scholar]
  8. 8. 
    Bertholet AM, Kazak L, Chouchani ET, Bogaczynska MG, Paranjpe I et al. 2017. Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine cycling. Cell Metab 25:811–22.e4
    [Google Scholar]
  9. 9. 
    Bouillaud F, Weissenbach J, Ricquier D. 1986. Complete cDNA-derived amino acid sequence of rat brown fat uncoupling protein. J. Biol. Chem. 261:1487–90
    [Google Scholar]
  10. 10. 
    Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. 2013. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep 5:1196–203
    [Google Scholar]
  11. 11. 
    McLaughlin SG, Dilger JP. 1980. Transport of protons across membranes by weak acids. Physiol. Rev. 60:825–63
    [Google Scholar]
  12. 12. 
    Terada H. 1990. Uncouplers of oxidative phosphorylation. Environ. Health Perspect. 87:213–18
    [Google Scholar]
  13. 13. 
    Harper JA, Dickinson K, Brand MD. 2001. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes. Rev. 2:255–65
    [Google Scholar]
  14. 14. 
    Tainter ML, Cutting WC, Hines E. 1935. Effect of moderate doses of dinitrophenol on the energy exchange and nitrogen metabolism of patients under conditions of restricted dietary. J. Pharmacol. Exp. Ther. 55:326–53
    [Google Scholar]
  15. 15. 
    Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2011. 2: 4-Dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J. Med. Toxicol. 7:205–12
    [Google Scholar]
  16. 16. 
    Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. 2015. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347:1253–56
    [Google Scholar]
  17. 17. 
    Szabo I, Leanza L, Gulbins E, Zoratti M 2012. Physiology of potassium channels in the inner membrane of mitochondria. Pflügers Arch 463:231–46
    [Google Scholar]
  18. 18. 
    Rasola A, Sciacovelli M, Pantic B, Bernardi P. 2010. Signal transduction to the permeability transition pore. FEBS Lett 584:1989–96
    [Google Scholar]
  19. 19. 
    Divakaruni AS, Brand MD. 2011. The regulation and physiology of mitochondrial proton leak. Physiology 26:192–205
    [Google Scholar]
  20. 20. 
    Garlid KD, Jaburek M, Jezek P. 2001. Mechanism of uncoupling protein action. Biochem. Soc. Trans. 29:803–6
    [Google Scholar]
  21. 21. 
    Klingenberg M, Huang SG. 1999. Structure and function of the uncoupling protein from brown adipose tissue. Biochim. Biophys. Acta 1415:271–96
    [Google Scholar]
  22. 22. 
    Bertholet AM, Chouchani ET, Kazak L, Angelin A, Fedorenko A et al. 2019. H+ transport is an integral function of the mitochondrial ADP/ATP carrier. Nature 571:515–20
    [Google Scholar]
  23. 23. 
    Fedorenko A, Lishko PV, Kirichok Y. 2012. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400–13
    [Google Scholar]
  24. 24. 
    Bertholet AM, Kirichok Y. 2020. Patch-clamp analysis of the mitochondrial H+ leak in brown and beige fat. Front. Physiol. 11:326
    [Google Scholar]
  25. 25. 
    Ricquier D, Kader JC. 1976. Mitochondrial protein alteration in active brown fat: a sodium dodecyl sulfate-polyacrylamide gel electrophoretic study. Biochem. Biophys. Res. Commun. 73:577–83
    [Google Scholar]
  26. 26. 
    Nicholls DG. 2001. A history of UCP1. Biochem. Soc. Trans. 29:751–55
    [Google Scholar]
  27. 27. 
    Heaton GM, Wagenvoord RJ, Kemp A Jr., Nicholls DG. 1978. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur. J. Biochem. 82:515–21
    [Google Scholar]
  28. 28. 
    Andreyev A, Bondareva TO, Dedukhova VI, Mokhova EN, Skulachev VP, Volkov NI. 1988. Carboxyatractylate inhibits the uncoupling effect of free fatty acids. FEBS Lett 226:265–69
    [Google Scholar]
  29. 29. 
    Andreyev A, Bondareva TO, Dedukhova VI, Mokhova EN, Skulachev VP et al. 1989. The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria. Eur. J. Biochem. 182:585–92
    [Google Scholar]
  30. 30. 
    Skulachev VP. 1991. Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett 294:158–62
    [Google Scholar]
  31. 31. 
    Klingenberg M. 2008. The ADP and ATP transport in mitochondria and its carrier. Biochim. Biophys. Acta 1778:1978–2021
    [Google Scholar]
  32. 32. 
    Brustovetsky N, Klingenberg M. 1996. Mitochondrial ADP/ATP carrier can be reversibly converted into a large channel by Ca2+. Biochemistry 35:8483–88
    [Google Scholar]
  33. 33. 
    Hunter DR, Haworth RA. 1979. The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch. Biochem. Biophys. 195:453–59
    [Google Scholar]
  34. 34. 
    Le Quoc K, Le Quoc D 1988. Involvement of the ADP/ATP carrier in calcium-induced perturbations of the mitochondrial inner membrane permeability: importance of the orientation of the nucleotide binding site. Arch. Biochem. Biophys. 265:249–57
    [Google Scholar]
  35. 35. 
    Schonfeld P, Bohnensack R. 1997. Fatty acid-promoted mitochondrial permeability transition by membrane depolarization and binding to the ADP/ATP carrier. FEBS Lett 420:167–70
    [Google Scholar]
  36. 36. 
    Wieckowski MR, Wojtczak L. 1998. Fatty acid-induced uncoupling of oxidative phosphorylation is partly due to opening of the mitochondrial permeability transition pore. FEBS Lett 423:339–42
    [Google Scholar]
  37. 37. 
    Stepien G, Torroni A, Chung AB, Hodge JA, Wallace DC 1992. Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation. J. Biol. Chem. 267:14592–97
    [Google Scholar]
  38. 38. 
    Rodic N, Oka M, Hamazaki T, Murawski MR, Jorgensen M et al. 2005. DNA methylation is required for silencing of Ant4, an adenine nucleotide translocase selectively expressed in mouse embryonic stem cells and germ cells. Stem Cells 23:1314–23
    [Google Scholar]
  39. 39. 
    Levy SE, Chen YS, Graham BH, Wallace DC 2000. Expression and sequence analysis of the mouse adenine nucleotide translocase 1 and 2 genes. Gene 254:57–66
    [Google Scholar]
  40. 40. 
    Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC. 1997. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat. Genet. 16:226–34
    [Google Scholar]
  41. 41. 
    Brand MD, Pakay JL, Ocloo A, Kokoszka J, Wallace DC et al. 2005. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem. J. 392:353–62
    [Google Scholar]
  42. 42. 
    Morrow RM, Picard M, Derbeneva O, Leipzig J, McManus MJ et al. 2017. Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. PNAS 114:2705–10
    [Google Scholar]
  43. 43. 
    Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J et al. 2004. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–65
    [Google Scholar]
  44. 44. 
    Zackova M, Kramer R, Jezek P. 2000. Interaction of mitochondrial phosphate carrier with fatty acids and hydrophobic phosphate analogs. Int. J. Biochem. Cell Biol. 32:499–508
    [Google Scholar]
  45. 45. 
    Engstova H, Zackova M, Ruzicka M, Meinhardt A, Hanus J et al. 2001. Natural and azido fatty acids inhibit phosphate transport and activate fatty acid anion uniport mediated by the mitochondrial phosphate carrier. J. Biol. Chem. 276:4683–91
    [Google Scholar]
  46. 46. 
    Skulachev VP. 1998. Uncoupling: new approaches to an old problem of bioenergetics. Biochim. Biophys. Acta 1363:100–24
    [Google Scholar]
  47. 47. 
    Wieckowski MR, Wojtczak L. 1997. Involvement of the dicarboxylate carrier in the protonophoric action of long-chain fatty acids in mitochondria. Biochem. Biophys. Res. Commun. 232:414–17
    [Google Scholar]
  48. 48. 
    Wojtczak L, Wieckowski MR. 1999. The mechanisms of fatty acid-induced proton permeability of the inner mitochondrial membrane. J. Bioenerget. Biomembr. 31:447–55
    [Google Scholar]
  49. 49. 
    Halestrap AP, Richardson AP. 2015. The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J. Mol. Cell. Cardiol. 78:129–41
    [Google Scholar]
  50. 50. 
    Kwong JQ, Davis J, Baines CP, Sargent MA, Karch J et al. 2014. Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209–17
    [Google Scholar]
  51. 51. 
    Seifert EL, Gal A, Acoba MG, Li Q, Anderson-Pullinger L et al. 2016. Natural and induced mitochondrial phosphate carrier loss: differential dependence of mitochondrial metabolism and dynamics and cell survival on the extent of depletion. J. Biol. Chem. 291:26126–37
    [Google Scholar]
  52. 52. 
    Gutierrez-Aguilar M, Douglas DL, Gibson AK, Domeier TL, Molkentin JD, Baines CP. 2014. Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. J. Mol. Cell. Cardiol. 72:316–25
    [Google Scholar]
  53. 53. 
    Sinasac DS, Moriyama M, Jalil MA, Begum L, Li MX et al. 2004. Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol. Cell. Biol. 24:527–36
    [Google Scholar]
  54. 54. 
    Jalil MA, Begum L, Contreras L, Pardo B, Iijima M et al. 2005. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J. Biol. Chem. 280:31333–39
    [Google Scholar]
  55. 55. 
    Llorente-Folch I, Rueda CB, Amigo I, del Arco A, Saheki T et al. 2013. Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J. Neurosci. 33:13957–71
    [Google Scholar]
  56. 56. 
    Fleury C, Neverova M, Collins S, Raimbault S, Champigny O et al. 1997. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet. 15:269–72
    [Google Scholar]
  57. 57. 
    Gimeno RE, Dembski M, Weng X, Deng N, Shyjan AW et al. 1997. Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis. Diabetes 46:900–6
    [Google Scholar]
  58. 58. 
    Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A et al. 1997. Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 408:39–42
    [Google Scholar]
  59. 59. 
    Gong DW, He Y, Karas M, Reitman M 1997. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, β3-adrenergic agonists, and leptin. J. Biol. Chem. 272:24129–32
    [Google Scholar]
  60. 60. 
    Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB. 1997. UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem. Biophys. Res. Commun. 235:79–82
    [Google Scholar]
  61. 61. 
    Jaburek M, Garlid KD. 2003. Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10. J. Biol. Chem. 278:25825–31
    [Google Scholar]
  62. 62. 
    Jaburek M, Varecha M, Gimeno RE, Dembski M, Jezek P et al. 1999. Transport function and regulation of mitochondrial uncoupling proteins 2 and 3. J. Biol. Chem. 274:26003–7
    [Google Scholar]
  63. 63. 
    Nedergaard J, Cannon B. 2003. The ‘novel’ ‘uncoupling’ proteins UCP2 and UCP3: What do they really do? Pros and cons for suggested functions. Exp. Physiol. 88:65–84
    [Google Scholar]
  64. 64. 
    Krauss S, Zhang CY, Lowell BB. 2005. The mitochondrial uncoupling-protein homologues. Nat. Rev. 6:248–61
    [Google Scholar]
  65. 65. 
    Bouillaud F, Alves-Guerra MC, Ricquier D. 2016. UCPs, at the interface between bioenergetics and metabolism. Biochim. Biophys. Acta 1863:2443–56
    [Google Scholar]
  66. 66. 
    Brand MD, Esteves TC. 2005. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2:85–93
    [Google Scholar]
  67. 67. 
    Criscuolo F, Mozo J, Hurtaud C, Nubel T, Bouillaud F 2006. UCP2, UCP3, avUCP, what do they do when proton transport is not stimulated? Possible relevance to pyruvate and glutamine metabolism. Biochim. Biophys. Acta 1757:1284–91
    [Google Scholar]
  68. 68. 
    Bouillaud F. 2009. UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing. Biochim. Biophys. Acta 1787:377–83
    [Google Scholar]
  69. 69. 
    Vozza A, Parisi G, De Leonardis F, Lasorsa FM, Castegna A et al. 2014. UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. PNAS 111:960–65
    [Google Scholar]
  70. 70. 
    Skulachev VP. 1999. Anion carriers in fatty acid-mediated physiological uncoupling. J. Bioenerget. Biomembr. 31:431–45
    [Google Scholar]
  71. 71. 
    Chouchani ET, Kazak L, Spiegelman BM. 2019. New advances in adaptive thermogenesis: UCP1 and beyond. Cell Metab 29:27–37
    [Google Scholar]
  72. 72. 
    Pfeifer A, Hoffmann LS. 2015. Brown, beige, and white: the new color code of fat and its pharmacological implications. Annu. Rev. Pharmacol. Toxicol. 55:207–27
    [Google Scholar]
  73. 73. 
    Smith RE, Roberts JC, Hittelman KJ. 1966. Nonphosphorylating respiration of mitochondria from brown adipose tissue of rats. Science 154:653–54
    [Google Scholar]
  74. 74. 
    Nicholls DG, Lindberg O. 1973. Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities. Eur. J. Biochem. 37:523–30
    [Google Scholar]
  75. 75. 
    Nicholls DG, Rial E. 1999. A history of the first uncoupling protein, UCP1. J. Bioenerget. Biomembr. 31:399–406
    [Google Scholar]
  76. 76. 
    Klingenberg M. 2017. UCP1—a sophisticated energy valve. Biochimie 134:19–27
    [Google Scholar]
  77. 77. 
    Bertholet AM, Kirichok Y. 2017. UCP1: a transporter for H+ and fatty acid anions. Biochimie 134:28–34
    [Google Scholar]
  78. 78. 
    Decoursey TE. 2003. Voltage-gated proton channels and other proton transfer pathways. Physiol. Rev. 83:475–579
    [Google Scholar]
  79. 79. 
    Kozak LP, Koza RA, Anunciado-Koza R. 2010. Brown fat thermogenesis and body weight regulation in mice: relevance to humans. Int. J. Obes. 34:Suppl. 1S23–27
    [Google Scholar]
  80. 80. 
    Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. 2012. Recruited versus nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 302:E19–31
    [Google Scholar]
  81. 81. 
    Wu J, Cohen P, Spiegelman BM. 2013. Adaptive thermogenesis in adipocytes: Is beige the new brown?. Genes Dev 27:234–50
    [Google Scholar]
  82. 82. 
    Wu J, Bostrom P, Sparks LM, Ye L, Choi JH et al. 2012. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–76
    [Google Scholar]
  83. 83. 
    Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K et al. 2015. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163:643–55
    [Google Scholar]
  84. 84. 
    Rolfe DF, Brand MD 1996. Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. Am. J. Physiol. 271:C1380–89
    [Google Scholar]
  85. 85. 
    Rolfe DF, Newman JM, Buckingham JA, Clark MG, Brand MD 1999. Contribution of mitochondrial proton leak to respiration rate in working skeletal muscle and liver and to SMR. Am. J. Physiol. 276:C692–99
    [Google Scholar]
  86. 86. 
    Brand MD, Chien LF, Ainscow EK, Rolfe DF, Porter RK 1994. The causes and functions of mitochondrial proton leak. Biochim. Biophys. Acta 1187:132–39
    [Google Scholar]
  87. 87. 
    Cho J, Seo J, Lim CH, Yang L, Shiratsuchi T et al. 2015. Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis. Cell Death Differ 22:1437–50
    [Google Scholar]
  88. 88. 
    Schonfeld P. 1990. Does the function of adenine nucleotide translocase in fatty acid uncoupling depend on the type of mitochondria?. FEBS Lett 264:246–48
    [Google Scholar]
  89. 89. 
    Wojtczak L, Schonfeld P. 1993. Effect of fatty acids on energy coupling processes in mitochondria. Biochim. Biophys. Acta 1183:41–57
    [Google Scholar]
  90. 90. 
    Garlid KD, Halestrap AP. 2012. The mitochondrial KATP channel—fact or fiction?. J. Mol. Cell. Cardiol. 52:578–83
    [Google Scholar]
  91. 91. 
    Samartsev VN, Smirnov AV, Zeldi IP, Markova OV, Mokhova EN, Skulachev VP. 1997. Involvement of aspartate/glutamate antiporter in fatty acid-induced uncoupling of liver mitochondria. Biochim. Biophys. Acta 1319:251–57
    [Google Scholar]
  92. 92. 
    Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB et al. 2008. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–23
    [Google Scholar]
  93. 93. 
    Da Cruz S, Xenarios I, Langridge J, Vilbois F, Parone PA, Martinou JC 2003. Proteomic analysis of the mouse liver mitochondrial inner membrane. J. Biol. Chem. 278:41566–71
    [Google Scholar]
  94. 94. 
    Cunningham SA, Wiesinger H, Nicholls DG. 1986. Quantification of fatty acid activation of the uncoupling protein in brown adipocytes and mitochondria from the guinea-pig. Eur. J. Biochem. 157:415–20
    [Google Scholar]
  95. 95. 
    Parker N, Crichton PG, Vidal-Puig AJ, Brand MD. 2009. Uncoupling protein-1 (UCP1) contributes to the basal proton conductance of brown adipose tissue mitochondria. J. Bioenerget. Biomembr. 41:335–42
    [Google Scholar]
  96. 96. 
    Rauckhorst AJ, Broekemeier KM, Pfeiffer DR. 2014. Regulation of the Ca2+-independent phospholipase A2 in liver mitochondria by changes in the energetic state. J. Lipid Res. 55:826–36
    [Google Scholar]
  97. 97. 
    Seleznev K, Zhao C, Zhang XH, Song K, Ma ZA 2006. Calcium-independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine. J. Biol. Chem. 281:22275–88
    [Google Scholar]
  98. 98. 
    Gadd ME, Broekemeier KM, Crouser ED, Kumar J, Graff G, Pfeiffer DR. 2006. Mitochondrial iPLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition. J. Biol. Chem. 281:6931–39
    [Google Scholar]
  99. 99. 
    Szabo I, Zoratti M. 2014. Mitochondrial channels: ion fluxes and more. Physiol. Rev. 94:519–608
    [Google Scholar]
  100. 100. 
    Hulsmann WC, Elliott WB, Slater EC 1960. The nature and mechanism of action of uncoupling agents present in mitochrome preparations. Biochim. Biophys. Acta 39:267–76
    [Google Scholar]
  101. 101. 
    Lardy HA, Pressman BC. 1956. Effect of surface active agents on the latent ATPase of mitochondria. Biochim. Biophys. Acta 21:458–66
    [Google Scholar]
  102. 102. 
    Wojtczak L, Wojtczak AB. 1960. Uncoupling of oxidative phosphorylation and inhibition of ATP-Pi exchange by a substance from insect mitochondria. Biochim. Biophys. Acta 39:277–86
    [Google Scholar]
  103. 103. 
    Lindberg O, de Pierre J, Rylander E, Afzelius BA 1967. Studies of the mitochondrial energy-transfer system of brown adipose tissue. J. Cell Biol. 34:293–310
    [Google Scholar]
  104. 104. 
    Hittelman KJ, Lindberg O, Cannon B. 1969. Oxidative phosphorylation and compartmentation of fatty acid metabolism in brown fat mitochondria. Eur. J. Biochem. 11:183–92
    [Google Scholar]
  105. 105. 
    Rafael J, Ludolph HJ, Hohorst HJ. 1969. Mitochondria from brown adipose tissue: uncoupling of respiratory chain phosphorylation by long fatty acids and recoupling by guanosine triphosphate. Hoppe-Seyler's Z. Physiol. Chem. 350:1121–31
    [Google Scholar]
  106. 106. 
    Grav HI, Blix AS. 1979. A source of nonshivering thermogenesis in fur seal skeletal muscle. Science 204:87–89
    [Google Scholar]
  107. 107. 
    Cannon B, Sundin U, Romert L. 1977. Palmitoyl coenzyme A: a possible physiological regulator of nucleotide binding to brown adipose tissue mitochondria. FEBS Lett 74:43–46
    [Google Scholar]
  108. 108. 
    Echtay KS, Winkler E, Klingenberg M. 2000. Coenzyme Q is an obligatory cofactor for uncoupling protein function. Nature 408:609–13
    [Google Scholar]
  109. 109. 
    Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ et al. 2003. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J 22:4103–10
    [Google Scholar]
  110. 110. 
    Nicholls DG, Locke RM. 1984. Thermogenic mechanisms in brown fat. Physiol. Rev. 64:1–64
    [Google Scholar]
  111. 111. 
    Shabalina IG, Petrovic N, Kramarova TV, Hoeks J, Cannon B, Nedergaard J. 2006. UCP1 and defense against oxidative stress: 4-hydroxy-2-nonenal effects on brown fat mitochondria are uncoupling protein 1-independent. J. Biol. Chem. 281:13882–93
    [Google Scholar]
  112. 112. 
    Locke RM, Rial E, Scott ID, Nicholls DG 1982. Fatty acids as acute regulators of the proton conductance of hamster brown-fat mitochondria. Eur. J. Biochem. 129:373–80
    [Google Scholar]
  113. 113. 
    Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M. 2020. Free fatty acid receptors in health and disease. Physiol. Rev. 100:171–210
    [Google Scholar]
  114. 114. 
    Houten SM, Violante S, Ventura FV, Wanders RJ 2016. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu. Rev. Physiol. 78:23–44
    [Google Scholar]
  115. 115. 
    Scarpa A, Lindsay JG. 1972. Maintenance of energy-linked functions in rat-liver mitochondria aged in the presence of nupercaine. Eur. J. Biochem. 27:401–7
    [Google Scholar]
  116. 116. 
    Parce JW, Cunningham CC, Waite M. 1978. Mitochondrial phospholipase A2 activity and mitochondrial aging. Biochemistry 17:1634–39
    [Google Scholar]
  117. 117. 
    Song H, Wohltmann M, Bao S, Ladenson JH, Semenkovich CF, Turk J. 2010. Mice deficient in group VIB phospholipase A2 (iPLA2γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet. Am. J. Physiol. Endocrinol. Metab. 298:E1097–114
    [Google Scholar]
  118. 118. 
    Mancuso DJ, Sims HF, Yang K, Kiebish MA, Su X et al. 2010. Genetic ablation of calcium-independent phospholipase A2γ prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation. J. Biol. Chem. 285:36495–510
    [Google Scholar]
  119. 119. 
    Levrat C, Louisot P. 1996. Increase of mitochondrial PLA2-released fatty acids is an early event in tumor necrosis factor α-treated WEHI-164 cells. Biochem. Biophys. Res. Commun. 221:531–8
    [Google Scholar]
  120. 120. 
    Broekemeier KM, Iben JR, LeVan EG, Crouser ED, Pfeiffer DR. 2002. Pore formation and uncoupling initiate a Ca2+-independent degradation of mitochondrial phospholipids. Biochemistry 41:7771–80
    [Google Scholar]
  121. 121. 
    Williams SD, Gottlieb RA. 2002. Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective. Biochem. J. 362:23–32
    [Google Scholar]
  122. 122. 
    Brustovetsky T, Antonsson B, Jemmerson R, Dubinsky JM, Brustovetsky N. 2005. Activation of calcium-independent phospholipase A2 (iPLA2) in brain mitochondria and release of apoptogenic factors by BAX and truncated BID. J. Neurochem. 94:980–94
    [Google Scholar]
  123. 123. 
    Zhu D, Lai Y, Shelat PB, Hu C, Sun GY, Lee JC. 2006. Phospholipases A2 mediate amyloid-β peptide-induced mitochondrial dysfunction. J. Neurosci. 26:11111–19
    [Google Scholar]
  124. 124. 
    Kinsey GR, McHowat J, Patrick KS, Schnellmann RG 2007. Role of Ca2+-independent phospholipase A2γ in Ca2+-induced mitochondrial permeability transition. J. Pharmacol. Exp. Ther. 321:707–15
    [Google Scholar]
  125. 125. 
    Jezek J, Jaburek M, Zelenka J, Jezek P. 2010. Mitochondrial phospholipase A2 activated by reactive oxygen species in heart mitochondria induces mild uncoupling. Physiol. Res. 59:737–47
    [Google Scholar]
  126. 126. 
    Blum JL, Kinsey GR, Monian P, Sun B, Cummings BS et al. 2011. Profiling of fatty acids released during calcium-induced mitochondrial permeability transition in isolated rabbit kidney cortex mitochondria. Toxicol. In Vitro 25:1001–6
    [Google Scholar]
  127. 127. 
    Winkler E, Klingenberg M. 1994. Effect of fatty acids on H+ transport activity of the reconstituted uncoupling protein. J. Biol. Chem. 269:2508–15
    [Google Scholar]
  128. 128. 
    Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P. 1996. On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J. Biol. Chem. 271:2615–20
    [Google Scholar]
  129. 129. 
    Brustovetsky N, Klingenberg M. 1994. The reconstituted ADP/ATP carrier can mediate H+ transport by free fatty acids, which is further stimulated by mersalyl. J. Biol. Chem. 269:27329–36
    [Google Scholar]
  130. 130. 
    Bieber LL, Pettersson B, Lindberg O 1975. Studies on norepinephrine-induced efflux of free fatty acid from hamster brown-adipose-tissue cells. Eur. J. Biochem. 58:375–81
    [Google Scholar]
  131. 131. 
    Fasano M, Curry S, Terreno E, Galliano M, Fanali G et al. 2005. The extraordinary ligand binding properties of human serum albumin. IUBMB Life 57:787–96
    [Google Scholar]
  132. 132. 
    Ruprecht JJ, Kunji ERS. 2020. The SLC25 mitochondrial carrier family: structure and mechanism. Trends Biochem. Sci. 45:244–58
    [Google Scholar]
  133. 133. 
    Robinson AJ, Overy C, Kunji ER. 2008. The mechanism of transport by mitochondrial carriers based on analysis of symmetry. PNAS 105:17766–71
    [Google Scholar]
  134. 134. 
    Ježek P, Špaček T, Garlid K, Jabůrek M 2006. Undecanesulfonate does not allosterically activate H+ uniport mediated by uncoupling protein-1 in brown adipose tissue mitochondria. Int. J. Biochem. Cell Biol. 38:1965–74
    [Google Scholar]
  135. 135. 
    Hamilton JA. 1998. Fatty acid transport: Difficult or easy?. J. Lipid Res. 39:467–81
    [Google Scholar]
  136. 136. 
    Ptak M, Egret-Charlier M, Sanson A, Bouloussa O 1980. A NMR study of the ionization of fatty acids, fatty amines and N-acylamino acids incorporated in phosphatidylcholine vesicles. Biochim. Biophys. Acta 600:387–97
    [Google Scholar]
  137. 137. 
    Guthrie JP. 1978. Hydrolysis of esters of oxy acids: pKa values for strong acids; Brønsted relationship for attack of water at methyl; free energies of hydrolysis of esters of oxy acids; and a linear relationship between free-energy of hydrolysis and pKa holding over a range of 20 pK units. Can. J. Chem. 56:2342–54
    [Google Scholar]
  138. 138. 
    Kunji ER, Aleksandrova A, King MS, Majd H, Ashton VL et al. 2016. The transport mechanism of the mitochondrial ADP/ATP carrier. Biochim. Biophys. Acta 1863:2379–93
    [Google Scholar]
  139. 139. 
    Huang SG. 2003. Binding of fatty acids to the uncoupling protein from brown adipose tissue mitochondria. Arch. Biochem. Biophys. 412:142–46
    [Google Scholar]
  140. 140. 
    Nicholls DG. 2006. The physiological regulation of uncoupling proteins. Biochim. Biophys. Acta 1757:459–66
    [Google Scholar]
  141. 141. 
    Rial E, Poustie A, Nicholls DG 1983. Brown-adipose-tissue mitochondria: the regulation of the 32 000-Mr uncoupling protein by fatty acids and purine nucleotides. Eur. J. Biochem. 137:197–203
    [Google Scholar]
  142. 142. 
    Shabalina IG, Jacobsson A, Cannon B, Nedergaard J. 2004. Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J. Biol. Chem. 279:38236–48
    [Google Scholar]
  143. 143. 
    Korshunov SS, Skulachev VP, Starkov AA. 1997. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416:15–18
    [Google Scholar]
  144. 144. 
    Caldeira da Silva CC, Cerqueira FM, Barbosa LF, Medeiros MH, Kowaltowski AJ 2008. Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7:552–60
    [Google Scholar]
  145. 145. 
    Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ et al. 2004. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic. . Biol. Med. 37:755–67
    [Google Scholar]
  146. 146. 
    Brand MD. 2016. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. . Biol. Med. 100:14–31
    [Google Scholar]
  147. 147. 
    Liu SS. 1999. Cooperation of a “reactive oxygen cycle” with the Q cycle and the proton cycle in the respiratory chain–superoxide generating and cycling mechanisms in mitochondria. J. Bioenerget. Biomembr. 31:367–76
    [Google Scholar]
  148. 148. 
    Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S et al. 2002. Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99
    [Google Scholar]
  149. 149. 
    Xiao H, Jedrychowski MP, Schweppe DK, Huttlin EL, Yu Q et al. 2020. A quantitative tissue-specific landscape of protein redox regulation during aging. Cell 180:968–83.e24
    [Google Scholar]
  150. 150. 
    Chouchani ET, Kazak L, Jedrychowski MP, Lu GZ, Erickson BK et al. 2016. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 532:112–16
    [Google Scholar]
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