Role of Mitochondria in Alcoholic Liver Disease

Current Pathobiology Reports

Volumn 1, Issue 3, 2013, Pages 159-168

  García Ruiz, Carmen ^a   Kaplowitz, Neil ^b   Fernandez Checa, José C ^a,b  

^a INST D INVESTIGACIONS B   (Spain)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

ER Stress; Mitochondrial biogenesis; Mitochondrial cholesterol; Mitochondrial dynamics; Mitochondrial GSH; Mitochondrial protein acetylation

Indexed keywords

EID: 84899582553     PISSN: None     EISSN: 2167485X     Source Type: Journal    
DOI: 10.1007/s40139-013-0021-z     Document Type: Review

References (102)

1. Lucey MR, Mathurin P, Morgan TR (2006) Alcoholic hepatitis. New Engl J Med 360:2758–2769
2. Gao B, Bataller R (2011) Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141:1572–1585
3. Chen X, Sebastian B, Tang H (2009) Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 49:1554–1562
4. Kaplowitz N, Than TA, Shinohara M, Ji C (2007) Endoplasmic reticulum stress and liver injury. Semin Liver Dis 27:367–377
5. Mato JM, Martinez-Chantar ML, Lu SC (2008) Methionine metabolism and liver disease. Annu Rev Nutr 28:273–293
6. Donohue DM Jr (2009) Autophagy and ethanol-induced liver injury. World J Gastroenterol 15:1178–1185
7. Wu D, Cederbaum AI (2009) Oxidative stress and alcoholic liver disease. Semin Liver Dis 29(2):141–154
8. Colell A, García-Ruiz C, Miranda M, Ardite E, Marí M, Morales A, Corrales F, Kaplowitz N, Fernández-Checa JC (1998) Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 115:1541–1551
9. Pastorino JG, Hoek JB (2000) Ethanol potentiates tumor necrosis factor-alpha cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology 31:1141–1152
10. Bruguera M, Bertran A, Bombi JA, Rodes J (1977) Giant mitochondria in hepatocytes: a diagnostic hint for alcoholic liver disease. Gastroenterology 73:1383–1887
11. Chedid A, Mendenhall CL, Tosch T, Chen T, Rabin L, Garcia-Pont P, Goldberg SJ, Kiernan T, Seeff LB, Sorrell M et al (1986) Significance of megamitochondria in alcoholic liver disease. Gastroenterology 90:1858–1864
12. Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker WD Jr (1999) Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 31:430–434
13. Fromenty B, Grimbert S, Mansouri A, Beaugrand M, Erlinger S, Rötig A, Pessayre D (1995) Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis. Gastroenterology 108:193–200
14. Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122:2049–2063
15. Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368
16. Murgia M, Giorgi C, Pinton P, Rizzuto R (2009) Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. J Mol Cell Cardiol 46:781–788
17. Murphy MRP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13
18. 13 C]ketoisocaproate is impaired in alcoholics. Alcohol Clin Exp Res 18:951–955
19. Jenkins WJ, Peters TJ (1978) Mitochondrial enzyme activities in liver biopsies from patients with alcoholic liver disease. Gut 19:341–344
20. Rubin E, Beattie DS, Lieber CS (1970) Effects of ethanol on the biogenesis of mitochondrial membranes and associated mitochondrial functions. Lab Invest 23:620–627
21. Bernstein JD, Penniall R (1978) Effects of chronic ethanol treatment upon rat liver mitochondria. Biochem Pharmacol 27:2337–2342
22. Cederbaum AI, Lieber CS, Rubin E (1974) Effects of chronic ethanol treatment of mitochondrial functions damage to coupling site I. Arch Biochem Biophys 165:560–569
23. Spach PI, Cunningham CC (1987) Control of state 3 respiration in liver mitochondria from rats subjected to chronic ethanol consumption. Biochim Biophys Acta 894:460–467
24. • Chacko BK, Srivastava A, Johnson MS, Benavides GA, Chang MJ, Ye Y, Jhala N, Murphy MP, Kalyanaraman B, Darley-Usmar VM (2011) Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis. Hepatology 54:153–63. This study reports the effect of a mitochondrial-targeted antioxidant in the prevention of steatosis and hypoxia in alcohol fed rats
25. Cunningham CC, Coleman WB, Spach PI (1990) The effects of chronic ethanol consumption on hepatic mitochondrial energy metabolism. Alcohol Alcohol 25:127–136
26. Venkatraman A, Landar A, Davis AJ, Chamlee L, Sanderson T, Kim H, Page G, Pompilius M, Ballinger S, Darley-Usmar V, Bailey SM (2004) Modification of the mitochondrial proteome in response to the stress of ethanol-dependent hepatotoxicity. J Biol Chem 279:22092–22101
27. Cahill A, Cunningham CC (2000) Effects of chronic ethanol feeding on the protein composition of mitochondrial ribosomes. Electrophoresis 21:3420–3426
28. Bailey SM, Robinson G, Pinner A, Chamlee L, Ulasova E, Pompilius M et al (2006) S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver. Am J Physiol Gastrointest Liver Physiol 291:G857–G867
29. Lee JH, Yang ES, Park JW (2003) Inactivation of NADPH-dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury. J Biol Chem 278:51360–51371
30. Baraona E, Zeballos GA, Shoichet L, Mak KM, Lieber CS (2002) Ethanol consumption increases nitric oxide production in rats, and its peroxyni-trite-mediated toxicity is attenuated by polyenylphosphatidylcholine. Alcohol Clin Exp Res 26:883–889
31. (2+) -mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver. Am J Physiol Gastrointest Liver Physiol 299:G954–G966
32. Pastorino JG, Marcineviciute A, Cahill A, Hoek JB (1999) Potentiation by chronic ethanol treatment of the mitochondrial permeability transition. Biochem Biophys Res Commun 265:405–409
33. Venkatraman A, Shiva S, Wigley A, Ulasova E, Chhieng D, Bailey SM, Darley-Usmar VM (2004) The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice. Hepatology 40:565–573
34. Zhang X, Tachibana S, Wang H, Hisada M, Williams GM, Gao B, Sun Z (2010) Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice. Hepatology 52:2137–2147
35. •• Han D, Ybanez MD, Johnson HS, et al (2012) Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations. J Biol Chem 287:42165–42179. This study characterizes the increased mitochondrial respiratory capacity and biogenesis in liver of mice fed alcohol, which intriguingly correlate with increased liver injury
36. Jäger S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci USA 104:12017–12022
37. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434:113–118
38. Baur JA, Pearson KJ, Price NL et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342
39. Shen Z, Ajmo JM, Rogers CQ, Liang X, Le L, Murr MM, Peng Y, You M (2009) Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-α production in cultured macrophage cell lines. Am J Physiol Gastrointest Liver Physiol 296:G1047–G1053
40. Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD et al (2007) Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131:476–491
41. •• Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469: 221–224. This study demonstrates that mitochondrial oxidative stress and ROS generation result in the recruitment of NLRP3 and subsequent inflammation activation
42. • Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menas V, Barrieaud M, Min SY, Kurt-Jones EA, Szabo G (2012) IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 122:3476–3489. This study identifies the caspase 1 activation as an important mechanism of IL-1β generation and ALD
43. Bailey SM, Cunningham CC (2002) Contribution of mitochondria to oxidative stress associated with alcoholic liver disease. Free Radic Biol Med 32:11–16
44. Wu D, Cederbaum AE (2009) Oxidative stress and alcoholic liver disease. Semin Liver Dis 29:141–154
45. • Wang X, Wu D, Yang L, Gan L, Cederbaum AI. CYP2E1 Potentiates Ethanol-induction of Hypoxia and HIF-1α in vivo. Free Rad Biol Med 2013 May 10. doi: 10.1016/j.freeradbiomed.2013.05.009. This paper demonstrates a critical role for CYP2E1 in the potentiation of alcohol on hypoxia and HIF-1α activation, and that HIF-1α inhibition prevents these effects
46. Knockaert L, Fromenty B, Robi MA (2011) Mechanisms of mitochondrial targeting of cytochrome P4502E1: physiopathological role in liver injury and obesity. FEBS J 278:4252–4260
47. Robin MA, Sauvage I, Grandperret T, Descatoire V, Pessayre D, Fromenty B (2005) Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes. FEBS Lett 579:6895–6902
48. Bansal S, Liu CP, Sepuri NB et al (2010) Mitochondria-targeted cytochrome P450 2E1 induces oxidative damage and augments alcohol-mediated oxidative stress. J Biol Chem 285:24609–24619
49. Mari M, Colell A, Morales A et al (2009) Redox control of liver function in health and disease. Antioxid Redox Signal 12:1295–1331
50. Giorgio et al (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122:221–233
51. Koch OR, Fusco S, Ranieri SC, Maulucci G, Palozza P, Larocca LM, Cravero AA, Farre’ SM, De Spirito M, Galeotti T, Pani G (2008) Role of the life span determinant P66(shcA) in ethanol-induced liver damage. Lab Invest 88:750–760
52. Koch OR, De Leo ME, Borrello S et al (1994) Ethanol treatment up-regulates the expression of mitochondrial manganese superoxide dismutase in rat liver. Biochem Biophys Res Commun 201:1356–1365
53. Wheeler MD, Nakagami M, Bradford BU et al (2001) Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 276:36664–36672
54. Nanji AA, Griniuviene B, Sadrzadeh SM et al (1995) Effect of type of dietary fat and ethanol on antioxidant enzyme mRNA induction in rat liver. J Lipid Res 36:736–744
55. Degoul F, Sutton A, Mansouri A et al (2001) Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease. Gastroenterology 120:1468–1474
56. Hirano T, Kaplowitz N, Tsukamoto H, Kamimura S, Fernandez-Checa JC (1992) Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats. Hepatology 16:1423–1427
57. Garcia-Ruiz C, Morales A, Ballesta A et al (1994) Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest 94:193–201
58. Garcia-Ruiz C, Morales A, Colell A, Ballesta A, Rodes J, Kaplowitz N, Fernandez-Checa JC (1995) Feeding S-adenosyl-l-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology 21:207–214
59. Colell A, Coll O, García-Ruiz C, París R et al (2001) Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione. Hepatology 34:964–971
60. Zhao P, Kalhorn TF, Slattery JT (2002) Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver. Hepatology 36:326–335
61. Zhao P, Slattery JT (2002) Effects of ethanol dose and ethanol withdrawal on rat liver mitochondrial glutathione: implication of potentiated acetaminophen toxicity in alcoholics. Drug Metab Dispos 30:1413–1417
62. Guidot DM, Brown LAS (2000) Mitochondrial glutathione replacement restores surfactant synthesis and secretion in alveolar epithelial cells of ethanol-fed rats. Alcohol Clin Exp Res 24:1070–1076
63. • Fernandez A, Matias N, Fucho R, et al () ASMase is required for chronic alcohol induced hepatic endoplasmic reticulum stress and mitochondrial cholesterol loading. J Hepatol. doi: 10.1016/j.jhep.2013.05.023 This study demonstrates that ASMase links alcohol feeding to ER stress, and that this event is critical in causing mitochondrial cholesterol loading)
64. Josekutty J, Iqbal J, Iwawaki T et al (2013) Microsomal triglyceride transfer protein inhibition induces endoplasmic reticulum stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST. J Biol Chem 288:14372–14383
65. Ha SD, Park S, Han CY et al (2012) Cellular adaptation to anthrax lethal toxin-induced mitochondrial cholesterol enrichment, hyperpolarization, and reactive oxygen species generation through downregulating MLN64 in macrophages. Mol Cell Biol 32:4846–4860
66. •• von Montfort C, Matias N, Fernandez A, et al (2012) Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis. J Hepatol 57:852–859. This study illustrates the importance of a strict equilibrium between antioxidant enzymes in steatohepatitis
67. Mansouri A, Tarhuni A, Larosche I et al (2010) MnSOD overexpression prevents liver mitochondrial DNA depletion after an alcohol binge but worsens this effect after prolonged alcohol consumption in mice. Dig Dis 28:756–775
68. Malhi H, Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54:795–809
69. Fu S, Yang L, Li P, Hofmann O et al (2011) Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473:528–531
70. Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125–1131
71. Browning JD, Horton JD (2004) Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114:147–152
72. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430
73. Ji C, Kaplowitz N (2006) ER stress: can the liver cope? J Hepatol 45(2):321–333
74. Ji C, Kaplowitz N (2003) Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124(5):1488–1499
75. Kharbanda KK, Todero SL, King AL et al (2012) Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome. Int J Hepatol 2012:962183
76. Tsuchiya M, Ji C, Kosyk O et al (2012) Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice. Hepatology 56(1):130–139
77. • Boini KM, Xia M, Abais JM, et al (2012) Acid sphingomyelinase gene knockout ameliorates hyperhomocysteinemic glomerular injury in mice lacking cystathionine-b-synthase. PLoS One 7:e45020. This paper indicates that the deleterious effect of genetic hyperhomocysteinemia is dependent on the presence of acid sphingomyelinase
78. Caballero F, Fernández A, Matías N et al (2010) Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-l-methionine and glutathione. J Biol Chem 285:18528–18536
79. Henkel AS, Dewey AM, Anderson KA et al (2012) Reducing endoplasmic reticulum stress does not improve steatohepatitis in mice fed a methionine- and choline-deficient diet. Am J Physiol Gastrointest Liver Physiol 303:G54–G59
80. Marí M, Caballero F, Colell A et al (2006) Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 4:185–198
81. Mari M, Colell A, Morales A et al (2008) Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 134:1507–1520
82. Anuka E, Gal M, Stocco DM, Orly J (2013) Expression and roles of steroidogenic acute regulatory (StAR) protein in ‘non-classical’, extra-adrenal and extra-gonadal cells and tissues. Mol Cell Endocrinol 371:47–61
83. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461
84. Liesa M, Palacín M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89(3):799–845
85. Zorzano A, Sebastián D, Segalés J, Palacín M (2009) The molecular machinery of mitochondrial fusion and fission: an opportunity for drug discovery? Curr Opin Drug Discov Devel 12(5):597–606
86. Chan DC (2006) Dissecting mitochondrial fusion. Dev Cell 11:592–594
87. Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280(28):26185–26192
88. Shutt TE, McBride HM (2013) Staying cool in difficult times: mitochondrial dynamics, quality control and the stress response. Biochim Biophys Acta 1833(2):417–424
89. Agier V, Oliviero P, Lainé J et al (2012) Defective mitochondrial fusion, altered respiratory function, and distorted cristae structure in skin fibroblasts with heterozygous OPA1 mutations. Biochim Biophys Acta 1822(10):1570–1580
90. Zhang Z, Wakabayashi N, Wakabayashi J et al (2011) The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol Biol Cell 22:2235–2245
91. Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17:491–506
92. Das S, Hajnoczky N, Anthony AN et al (2012) Mitochondrial morphology and dynamics in hepatocytes from normal and ethanol-fed rats. Pfugers Arch 464:101–109
93. Mitra K, Wunder C, Roysam B et al (2009) A hyperfused mitochondrial state achieved at G1–S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci USA 106(29):11960–11965
94. •• Gomes, LC, Di Benedetto G, Scorrano,L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598. This study underscores the role of mitochondrial elongation on resistance to autophagy and increased ATP synthesis
95. Wasilewski M, Semenzato M, Rafelski SM et al (2012) Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts. Curr Biol 22:1228–1234
96. Huang JY, Hirschey MD, Shimazu T, Ho L, Verdin E (1804) Mitochondrial sirtuins. Biochim Biophys Acta 2010:1645–1651
97. Lombard DB, Alt FW, Cheng HL et al (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27:8807–8814
98. Hirschey MD, Shimazu T, Goetzman E et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125
99. Picklo MJ (2008) Ethanol intoxication increases hepatic N-lysyl protein acetylation. Biochim Biophys Res Commun 376(3):615–619
100. • Fritz KS, Galligan JJ, Smathers RL, et al (2011) 4-Hydroxynonenal inhibits SIRT3 via thiol-specific modification. Chem Res Toxicol 24: 651–662. This study provides novel mechanisms of SIRT3 inactivation, which has widespread implications in oxidative stress including alcoholic liver disease
101. Verdin E, Hirschey MD, Finley LW, Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35:669–675
102. Fritz KS, Galligan JJ, Hirschey MD et al (2012) Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice. J Proteom Res 11:1633–1643