Mitochondrial dysfunction in nonalcoholic steatohepatitis

Expert Review of Gastroenterology and Hepatology

Volumn 5, Issue 2, 2011, Pages 233-244

  Serviddio, Gaetano ^a   Bellanti, Francesco ^a   Vendemiale, Gianluigi ^a,b   Altomare, Emanuele ^a  

^a UNIVERSITY OF FOGGIA   (Italy)

^b CASA SOLLIEVO DELLA SOFFERENZA HOSPITAL   (Italy)

Author keywords

ATP homeostasis; fatty acid oxidation; HNE; mitochondria; NASH; reactive oxygen species; uncoupling

Indexed keywords

ADENINE NUCLEOTIDE TRANSLOCASE; CHYLOMICRON; CYTOCHROME C OXIDASE; MALONALDEHYDE; MITOCHONDRIAL PROTEIN; NITRIC OXIDE SYNTHASE; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATE SYNTHASE; REACTIVE OXYGEN METABOLITE; SUPEROXIDE DISMUTASE;

APOPTOSIS; BIOENERGY; CELL CYCLE ARREST; CELL DEATH; CELL FUNCTION; CELL STRUCTURE; CELL SURVIVAL; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENDOPLASMIC RETICULUM STRESS; FATTY ACID METABOLISM; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; GLYCOLYSIS; HOMEOSTASIS; HUMAN; HYDROLYSIS; LIPID METABOLISM; LIPID PEROXIDATION; LIVER MITOCHONDRION; MEMBRANE DEPOLARIZATION; MITOCHONDRIAL MEMBRANE; MITOCHONDRIAL PERMEABILITY; MITOCHONDRIAL RESPIRATION; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATION; OXIDATIVE PHOSPHORYLATION; OXIDATIVE PHOSPHORYLATION UNCOUPLING; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN SYNTHESIS; REVIEW; UPREGULATION;

ADENOSINE TRIPHOSPHATE; ANIMALS; ELECTRON TRANSPORT; ENERGY METABOLISM; FATTY LIVER; HUMANS; LIPID METABOLISM; LIPID PEROXIDATION; LIVER; MICE; MITOCHONDRIA, LIVER; MITOCHONDRIAL DISEASES; OXIDATIVE STRESS; RATS; REACTIVE OXYGEN SPECIES;

EID: 79954452625     PISSN: 17474124     EISSN: None     Source Type: Journal    
DOI: 10.1586/egh.11.11     Document Type: Review

References (149)

1. Lehninger AL. The Mitochondrion: Molecular Basis of Structure and Function. WA Benjamin, NY, USA (1965).
2. Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191, 144-148 (1961).
3. Frey TG, Mannella CA. The internal structure of mitochondria. Trends Biochem. Sci. 25, 319-324 (2000).
4. Endo T, Yamano K. Transport of proteins across or into the mitochondrial outer membrane. Biochim. Biophys. Acta 1803(6), 706-714. (2010).
5. Mannella CA. Structure and dynamics of the mitochondrial inner membrane cristae. Biochim. Biophys. Acta 1763, 542-548 (2006). (Pubitemid 44015951)
6. Srere PA. Citric acid cycle redux. Trends Biochem. Sci. 15, 411-412 (1990). (Pubitemid 20376574)
7. Forner F, Foster LJ, Campanaro S, Valle G, Mann M. Quantitative proteomic comparison of rat mitochondria from muscle, heart, and liver. Mol. Cell Proteomics. 5, 608-619 (2006).
8. Forman HJ, Maiorino M, Ursini F. Signaling functions of reactive oxygen species. Biochemistry 49, 835-842 (2010).
9. Rao MS, Reddy JK. Peroxisomal ß-oxidation and steatohepatitis. Semin. Liver Dis. 21, 43-55 (2001).
10. Bartlett K, Eaton S. Mitochondrial ß-oxidation. Eur. J. Biochem. 271, 462-469 (2004).
11. Schulz H. ß oxidation of fatty acids. Biochim. Biophys.Acta 1081, 109-120 (1991).
12. Eaton S. Control of mitochondrial ß-oxidation fux. Prog. LipidRes. 41, 197-239 (2002).
13. Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am. J. Physiol CellPhysiol 292, C670-C686 (2007).
14. Nicholls GC, Ferguson SJ. Bioenergetics: an Introduction to the Chemiosmotic Theory. Academy Press, NY, USA (1992)
15. Wallace DC Diseases of the mitochondrial DNA. Annu. Rev. Biochem. 61, 1175-1212 (1992).
16. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1, 642-645 (1989) (Pubitemid 19078788)
17. Wallace DC Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628-632 (1992).
18. Kadenbach B, Munscher C, Frank V, Muller-Hocker J, Napiwotzki J. Human aging is associated with stochastic somatic mutations of mitochondrial DNA. Mutat Res. 338, 161-172 (1995).
19. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 59, 527-605 (1979). (Pubitemid 9236599)
20. Gonzalez-Flecha B, Cutrin JC, Boveris A. Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J. Clin. Invest. 91, 456-464 (1993). (Pubitemid 23064129)
21. Lenaz G. The mitochondrial production of reactive oxygen species: mechanism and implications in human pathology. IUBMB Life 52, 159-164 (2001). (Pubitemid 33731569)
22. Loschen G, Azzi A, Richter C, Flohe L. Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett. 42, 68-72 (1974).
23. St Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J. Biol. Chem. 277, 44784-44790 (2002). (Pubitemid 36159072)
24. Skulachev VP. Uncoupling: new approaches to an old problem of bioenergetics. Biochim. Biophys. Acta 1363, 100-124 (1998). (Pubitemid 28129344)
25. Poli G, Schaur RJ. 4-Hydroxynonenal in the pathomechanisms of oxidative stress. IUBMB Life 50, 315-321 (2000). (Pubitemid 32289090)
26. Okuda M, Lee HC, Kumar C, Chance B. Comparison of the effect of a mitochondrial uncoupler, 2,4-dinitrophenol and adrenaline on oxygen radical production in the isolated perfused rat liver. Acta Physiol. Scand. 145, 159-168 (1992).
27. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416, 15-18 (1997). (Pubitemid 27470791)
28. Miwa S, St Pierre J, Partridge L, Brand MD. Superoxide and hydrogen peroxide production by Drosophila mitochondria. Free Radic Biol. Med. 35, 938-948 (2003). (Pubitemid 37211448)
29. Echtay KS, Esteves TC, Pakay JL et al. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. EMBO J. 22, 4103-4110 (2003). (Pubitemid 37021739)
30. Riahi Y, Cohen G, Shamni O, Sasson S. Signaling and cytotoxic functions of 4-hydroxyalkenals. Am. J. Physiol. Endocrinol. Metab. 299, E879-E886 (2010).
31. Fridovich I. Fundamental aspects of reactive oxygen species, or what s the matter with oxygen? Ann. NYAcad. Sci. 893, 13-18 (1999). (Pubitemid 30038064)
32. McCord JM. The evolution of free radicals and oxidative stress. Am. J. Med. 108, 652-659 (2000). (Pubitemid 30336605)
33. Bates TE, Loesch A, Burnstock G, Clark JB. Immunocytochemical evidence for a mitochondrially located nitric oxide synthase in brain and liver. Biochem. Biophys. Res. Commun. 213, 896-900 (1995).
34. Tatoyan A, Giulivi C Purifcation and characterization of a nitric-oxide synthase from rat liver mitochondria. J. Biol. Chem. 273, 11044-11048 (1998). (Pubitemid 28204948)
35. Venkatakrishnan P, Nakayasu ES, Almeida IC, Miller RT Absence of nitric-oxide synthase in sequentially purifed rat liver mitochondria. J. Biol. Chem. 284, 19843-19855 (2009).
36. Radi R, Cassina A, Hodara R, Quijano C, Castro L. Peroxynitrite reactions and formation in mitochondria. Free Radic Biol. Med. 33, 1451-1464 (2002). (Pubitemid 35351588)
37. Brookes PS, Kraus DW, Shiva S et al. Control of mitochondrial respiration by NO*, effects of low oxygen and respiratory state. J. Biol. Chem. 278, 31603-31609 (2003). (Pubitemid 37048338)
38. Stewart VC, Heales SJ. Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration. Free Radic Biol. Med. 34, 287-303 (2003). (Pubitemid 36120745)
39. Serviddio G, Bellanti F, Romano AD et al. Bioenergetics in aging: mitochondrial proton leak in aging rat liver, kidney and heart. Redox Rep. 12, 91-95 (2007). (Pubitemid 46210364)
40. + leak in mitochondria and its relevance to metabolic rate. Nature 362, 628-630 (1993). (Pubitemid 23109269)
41. Terada H. Uncouplers of oxidative phosphorylation. Environ. Health Perspect 87, 213-218 (1990). (Pubitemid 20316919)
42. Heytler PG. Uncouplers of oxidative phosphorylation. Pharmacol. Ther. 10, 461-472 (1980). (Pubitemid 11233580)
43. Kohnke D, Ludwig B, Kadenbach B. A threshold membrane potential accounts for controversial effects of fatty acids on mitochondrial oxidative phosphorylation. FEBS Lett. 336, 90-94 (1993). (Pubitemid 23362010)
44. Boss O, Muzzin P, Giacobino JP. The uncoupling proteins, a review. Eur. J. Endocrinol. 139, 1-9 (1998). (Pubitemid 28351225)
45. Kadenbach B. Intrinsic and extrinsic uncoupling of oxidative phosphorylation. Biochim. Biophys. Acta 1604, 77-94 (2003). (Pubitemid 36588693)
46. Larrouy D, Laharrague P, Carrera G et al. Kupffer cells are a dominant site of uncoupling protein 2 expression in rat liver. Biochem. Biophys. Res. Commun. 235, 760-764 (1997). (Pubitemid 27326558)
47. Chavin KD, Yang S, Lin HZ et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J. Biol. Chem. 274, 5692-5700 (1999). (Pubitemid 29109222)
48. Rashid A, Wu TC, Huang CC et al. Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver. Hepatology 29, 1131-1138 (1999). (Pubitemid 29168747)
49. Lanni A, Mancini FP, Sabatino L et al. De novo expression of uncoupling protein 3 is associated to enhanced mitochondrial thioesterase-1 expression and fatty acid metabolism in liver of fenofbrate-treated rats. FEBS Lett. 525, 7-12 (2002).
50. Silvestri E, de LP, Moreno M et al. Fenofbrate activates the biochemical pathways and the de novo expression of genes related to lipid handling and uncoupling protein-3 functions in liver of normal rats. Biochim. Biophys. Acta 1757, 486-495 (2006). (Pubitemid 43993838)
51. Kroemer G, Galluzzi L, Vandenabeele P et al. Classifcation of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16, 3-11 (2009).
52. Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl. J. Med. 361, 1570-1583 (2009).
53. Green DR, Reed JC. Mitochondria and apoptosis. Science 281, 1309-1312 (1998). (Pubitemid 28406816)
54. Smith DJ, Ng H, Kluck RM, Nagley P. The mitochondrial gateway to cell death. IUBMB Life 60, 383-389 (2008).
55. Jeong SY, Seol DW. The role of mitochondria in apoptosis. BMB Rep. 41, 11-22 (2008).
56. Harris MH, Thompson CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ. 7, 1182-1191 (2000). (Pubitemid 32042225)
57. Cesura AM, Pinard E, Schubenel R et al. The voltage-dependent anion channel is the target for a new class of inhibitors of the mitochondrial permeability transition pore. J. Biol. Chem. 278, 49812-49818 (2003). (Pubitemid 37548815)
58. Rasola A, Bernardi P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12, 815-833 (2007). (Pubitemid 46653292)
59. Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 134, 1641-1654 (2008). (Pubitemid 351615416)
60. Goldman SJ, Taylor R, Zhang Y, Jin S. Autophagy and the degradation of mitochondria. Mitochondrion 10(4), 309-315 (2010).
61. Baines CP, Kaiser RA, Purcell NH et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658-662 (2005). (Pubitemid 40488559)
62. Griffn EE, Chan DC Domain interactions within Fzo1 oligomers are essential for mitochondrial fusion. J. Biol. Chem. 281, 16599-16606 (2006).
63. Jagasia R, Grote P, Westermann B, Conradt B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C elegans. Nature 433, 754-760 (2005). (Pubitemid 40292985)
64. Youle RJ, Karbowski M. Mitochondrial fssion in apoptosis. Nat Rev. Mol. Cell Biol. 6, 657-663 (2005).
65. Baffy G. Uncoupling protein-2 and non-alcoholic fatty liver disease. Front Biosci. 10, 2082-2096 (2005). (Pubitemid 40908914)
66. Joshi B, Li L, Taffe BG et al. Apoptosis induction by a novel anti-prostate cancer compound, BMD188 (a fatty acid-containing hydroxamic acid), requires the mitochondrial respiratory chain. Cancer Res. 59, 4343-4355 (1999). (Pubitemid 29418753)
67. Matsuyama S, Llopis J, Deveraux QL, Tsien RY, Reed JC. Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis. Nat Cell Biol. 2, 318-325 (2000).
68. Camara Y, Mampel T, Armengol J, Villarroya F, Dejean L. UCP3 expression in liver modulates gene expression and oxidative metabolism in response to fatty acids, and sensitizes mitochondria to permeability transition. Cell Physiol Biochem. 24, 243-252 (2009).
69. Browning JD, Szczepaniak LS, Dobbins R et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387-1395 (2004). (Pubitemid 39657013)
70. Chitturi S, Farrell GC, Hashimoto E et al. Non-alcoholic fatty liver disease in the Asia-Pacifc region: defnitions and overview of proposed guidelines. J. Gastroenterol. Hepatol. 22, 778-787 (2007). (Pubitemid 46915352)
71. Patrick-Melin AJ, Kalinski MI, Kelly KR et al. Nonalcoholic fatty liver disease: biochemical and therapeutic considerations. Ukr. Biokhim. Zh. 81, 16-25 (2009).
72. Ratziu V, Caldwell S, Neuschwander-Tetri BA. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology 52, 2206-2215 (2010).
73. Pessayre D, Fromenty B. NASH: a mitochondrial disease. J. Hepatol. 42, 928-940 (2005). (Pubitemid 40693212)
74. Caldwell SH, Swerdlow RH, Khan EM et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J. Hepatol. 31, 430-434 (1999). (Pubitemid 29408724)
75. Sanyal AJ, Campbell-Sargent C, Mirshahi F et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 1183-1192 (2001). (Pubitemid 32246672)
76. Ahishali E, Demir K, Ahishali B et al. Electron microscopic fndings in non-alcoholic fatty liver disease: is there a difference between hepatosteatosis and steatohepatitis? J. Gastroenterol. Hepatol. 25, 619-626 (2010).
77. Le TH, Caldwell SH, Redick JA et al. The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis. Hepatology 39, 1423-1429 (2004). (Pubitemid 38569065)
78. Caldwell SH, de Freitas LA, Park SH et al. Intramitochondrial crystalline inclusions in nonalcoholic steatohepatitis. Hepatology 49, 1888-1895 (2009).
79. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim. Biophys. Acta 1302, 93-109 (1996). (Pubitemid 26247079)
80. Brady LJ, Brady PS, Romsos DR, Hoppel CL. Elevated hepatic mitochondrial and peroxisomal oxidative capacities in fed and starved adult obese (ob/ob) mice. Biochem. J. 231, 439-444 (1985). (Pubitemid 15244016)
81. Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T et al. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology 44, 581-591 (2006). (Pubitemid 44433714)
82. 13C-octanoate breath test. Am. J. Gastroenterol. 98, 2335-2336 (2003). (Pubitemid 37305387)
83. 13C-octanoate breath test for patients with nonalcoholic steatohepatitis using the BreathID system. Hepatogastroenterology 56, 1436-1438 (2009).
84. Yndestad A, Haukeland J W, Dahl TB et al. A complex role of activin A in non-alcoholic fatty liver disease. Am. J. Gastroenterol. 104, 2196-2205 (2009).
85. Lee Y, Wang MY, Kakuma T et al. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J. Biol. Chem. 276, 5629-5635 (2001).
86. Paterson JM, Morton NM, Fievet C et al. Metabolic syndrome without obesity: Hepatic overexpression of 11ß-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc. Natl Acad. Sci. USA 101, 7088-7093 (2004). (Pubitemid 38596447)
87. Pérez-Carreras M, Del Hoyo P, Martin MA et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38, 999-1007 (2003). (Pubitemid 37221683)
88. Nakamuta M, Kohjima M, Morizono S et al. Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int. J. Mol. Med. 16, 631-635 (2005).
89. Nagaya T, Tanaka N, Suzuki T et al. Down-regulation of SREBP-1c is associated with the development of burned-out NASH. J. Hepatol. 53, 724-731 (2010).
90. Stefanovic-Racic M, Perdomo G, Mantell BS et al. A moderate increase in carnitine palmitoyltransferase 1a activity is suffcient to substantially reduce hepatic triglyceride levels. Am. J. Physiol. Endocrinol. Metab. 294, E969-E977 (2008).
91. Akkaoui M, Cohen I, Esnous C et al. Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids. Biochem. J. 420, 429-438 (2009).
92. Koves TR, Ussher JR, Noland RC et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skelet al muscle insulin resistance. Cell Metab. 7, 45-56 (2008).
93. Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T et al. Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice. Hepatology 46, 414-423 (2007). (Pubitemid 47344776)
94. Petrosillo G, Portincasa P, Grattagliano I et al. Mitochondrial dysfunction in rat with nonalcoholic fatty liver Involvement of complex I, reactive oxygen species and cardiolipin. Biochim. Biophys. Acta 1767, 1260-1267 (2007). (Pubitemid 47498313)
95. Romestaing C, Piquet MA, Letexier D et al. Mitochondrial adaptations to steatohepatitis induced by a methionine-and choline-defcient diet. Am. J. Physiol. Endocrinol. Metab 294, E110-E119 (2008).
96. Haque M, Sanyal AJ. The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best. Pract. Res. Clin Gastroenterol. 16, 709-731 (2002).
97. Fromenty B, Pessayre D. Inhibition of mitochondrial ß-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101-154 (1995).
98. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 12, 1735-1744 (1998). (Pubitemid 28454438)
99. Flamment M, Arvier M, Gallois Y et al. Fatty liver and insulin resistance in obese Zucker rats: no role for mitochondrial dysfunction. Biochimie 90, 1407-1413 (2008).
100. + channel activity and reactive oxygen species generation. J. Bioenerg Biomembr. 42, 245-253 (2010).
101. Lieber CS, Leo MA, Mak KM et al. Model of nonalcoholic steatohepatitis. Am. J. Clin. Nutr. 79, 502-509 (2004). (Pubitemid 41115597)
102. Mantena SK, Vaughn DP, Andringa KK et al. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem. J. 417, 183-193 (2009).
103. Farrell GC, Larter CZ, Hou JY et al. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J. Gastroenterol. Hepatol. 24, 443-452 (2009).
104. Vendemiale G, Grattagliano I, Caraceni P et al. Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: effect of the nutritional status. Hepatology 33, 808-815 (2001). (Pubitemid 32246628)
105. Serviddio G, Bellanti F, Tamborra R et al. Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 57, 957-965 (2008). (Pubitemid 351919530)
106. Skulachev VP. Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q. Rev. Biophys. 29, 169-202 (1996). (Pubitemid 26280789)
107. Serviddio G, Bellanti F, Tamborra R et al. Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model. Eur. J. Clin. Invest 38, 245-252 (2008). (Pubitemid 351389142)
108. Ijaz S, Yang W, Winslet MC, Seifalian AM. The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental model of hepatic steatosis. Microvasc. Res. 70, 129-136 (2005). (Pubitemid 41586466)
109. Shiva S, Oh JY, Landar AL et al. Nitroxia: the pathological consequence of dysfunction in the nitric oxide-cytochrome c oxidase signaling pathway. Free Radic. Biol. Med. 38, 297-306 (2005). (Pubitemid 40075573)
110. Day CP, James OF. Steatohepatitis: a tale of two 'hits'? Gastroenterology 114, 842-845 (1998). (Pubitemid 28160420)
111. Cortez-Pinto H, de Moura MC, Day CP. Non-alcoholic steatohepatitis: from cell biology to clinical practice. J. Hepatol. 44, 197-208 (2006). (Pubitemid 41772535)
112. Demeilliers C, Maisonneuve C, Grodet A et al. Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice. Gastroenterology 123, 1278-1290 (2002).
113. Yin M, Gabele E, Wheeler MD et al. Alcohol-induced free radicals in mice: direct toxicants or signaling molecules? Hepatology 34, 935-942 (2001). (Pubitemid 33032028)
114. Sreekumar R, Rosado B, Rasmussen D, Charlton M. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology 38, 244-251 (2003). (Pubitemid 36775817)
115. Laurent A, Nicco C, Tran VN et al. Pivotal role of superoxide anion and benefcial effect of antioxidant molecules in murine steatohepatitis. Hepatology 39, 1277-1285 (2004). (Pubitemid 38569049)
116. Schattenberg JM, Singh R, Wang Y et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43, 163-172 (2006). (Pubitemid 43733603)
117. Nakamura S, Takamura T, Matsuzawa-Nagata N et al. Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J. Biol. Chem. 284, 14809-14818 (2009).
118. Nocito A, Dahm F, Jochum W et al. Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology 133, 608-618 (2007). (Pubitemid 47187345)
119. Videla LA, Rodrigo R, Orellana M et al. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin. Sci. (Lond.) 106, 261-268 (2004). (Pubitemid 38365832)
120. Boveris A, Oshino N, Chance B. The cellular production of hydrogen peroxide. Biochem. J. 128, 617-630 (1972).
121. Yang S, Zhu H, Li Y et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch. Biochem. Biophys. 378, 259-268 (2000). (Pubitemid 30397626)
122. Baffy G, Zhang CY, Glickman JN, Lowell BB. Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. Hepatology 35, 753-761 (2002). (Pubitemid 34258368)
123. Starkel P, Sempoux C, Leclercq I et al. Oxidative stress, KLF6 and transforming growth factor-b up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J. Hepatol. 39, 538-546 (2003). (Pubitemid 37204653)
124. Fulop P, Derdak Z, Sheets A et al. Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. Hepatology 44, 592-601 (2006). (Pubitemid 44433715)
125. Serviddio G, Pereda J, Pallardo FV et al. Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress. Hepatology 39, 711-720 (2004). (Pubitemid 38337650)
126. Negre-Salvayre A, Hirtz C, Carrera G et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 11, 809-815 (1997). (Pubitemid 27349566)
127. Evans ZP, Ellett JD, Schmidt MG, Schnellmann RG, Chavin KD. Mitochondrial uncoupling protein-2 mediates steatotic liver injury following ischemia/reperfusion. J. Biol. Chem. 283, 8573-8579 (2008).
128. Wan CD, Wang CY, Liu T, Cheng R, Wang HB. Alleviation of ischemia/reperfusion injury in ob/ob mice by inhibiting UCP-2 expression in fatty liver. World J. Gastroenterol. 14, 590-594 (2008). (Pubitemid 351320826)
129. Faggioni R, Shigenaga J, Moser A, Feingold KR, Grunfeld C. Induction of UCP2 gene expression by LPS: a potential mechanism for increased thermogenesis during infection. Biochem. Biophys. Res. Commun. 244, 75-78 (1998). (Pubitemid 28419903)
130. Hatano E, Tanaka A, Iwata S et al. Induction of endotoxin tolerance in transgenic mouse liver expressing creatine kinase. Hepatology 24, 663-669 (1996). (Pubitemid 26296013)
131. Donthamsetty S, Bhave VS, Mitra MS, Latendresse JR, Mehendale HM. Nonalcoholic fatty liver sensitizes rats to carbon tetrachloride hepatotoxicity. Hepatology 45, 391-403 (2007). (Pubitemid 46374596)
132. Nisoli E, Clementi E, Moncada S, Carruba MO. Mitochondrial biogenesis as a cellular signaling framework. Biochem. Pharmacol. 67, 1-15 (2004). (Pubitemid 37518530)
133. Feldstein AE, Canbay A, Angulo P et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125, 437-443 (2003). (Pubitemid 36929425)
134. Wieckowska A, Zein NN, Yerian LM et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44, 27-33 (2006). (Pubitemid 44049136)
135. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43, S99-S112 (2006).
136. Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43, S31-S44 (2006).
137. Oyanagi E, Yano H, Kato Y et al. l-carnitine suppresses oleic acid-induced membrane permeability transition of mitochondria. Cell Biochem. Funct. 26, 778-786 (2008).
138. Vendemiale G, Grattagliano I, Altomare E, Turturro N, Guerrieri F. Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat. Biochem. Pharmacol. 52, 1147-1154 (1996). (Pubitemid 26355290)
139. Anstee QM, Concas D, Kudo H et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53, 542-550 (2010).
140. Serviddio G, Bellanti F, Sastre J, Vendemiale G, Altomare E. Targeting mitochondria: a new promising approach for the treatment of liver diseases. Curr. Med. Chem. 17, 2325-2337 (2010).
141. Murphy MP. Selective targeting of bioactive compounds to mitochondria. Trends Biotechnol. 15, 326-330 (1997). (Pubitemid 27330629)
142. Domenicali M, Caraceni P, Vendemiale G et al. Food deprivation exacerbates mitochondrial oxidative stress in rat liver exposed to ischemia-reperfusion injury. J. Nutr. 131, 105-110 (2001). (Pubitemid 32060630)
143. Di Sario A, Bendia E, Taffetani S et al. Hepatoprotective and antifibrotic effect of a new silybin-phosphatidylcholine-vitamin E complex in rats. Dig. Liver Dis. 37, 869-876 (2005). (Pubitemid 44356117)
144. Loguercio C, Federico A, Trappoliere M et al. The effect of a silybin-vitamin E-phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig. Dis. Sci. 52, 2387-2395 (2007). (Pubitemid 47246522)
145. Serviddio G, Bellanti F, Giudetti AM et al. A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis. J. Pharmacol. Exp. Ther. 332, 922-932 (2010).
146. James AM, Sharpley MS, Manas AR et al. Interaction of the mitochondria-targeted antioxidant MitoQ with phospholipid bilayers and ubiquinone oxidoreductases. J. Biol. Chem. 282, 14708-14718 (2007). (Pubitemid 47093346)
147. Smith RA, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann. NY Acad. Sci. 1201, 96-103 (2010).
148. Ramirez-Tortosa MC, Ramirez-Tortosa CL, Mesa MD et al. Curcumin ameliorates rabbits's steatohepatitis via respiratory chain, oxidative stress, and TNF-a. Free Radic. Biol. Med. 47, 924-931 (2009).
149. Zhao K, Zhao GM, Wu D et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J. Biol. Chem. 279, 34682-34690 (2004). (Pubitemid 39318098)