CoChat
Sign Up
Cited by 122Alcohol Consumption and Health EffectsCoenzyme Q10 studies and effectsMitochondrial Function and Pathology

Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis

Open access
Chacko, Balu K., Srivastava, Anup, Johnson, Michelle S., Benavides, Gloria A., Chang, Mi Jung, Ye, Yaozu, Jhala, Nirag, Murphy, Michael P. +2 more·2011·Hepatology
DOI 10.1002/hep.24377PMC PMC3125473
Open this paper in CoChat — free accountOpen PDF

Abstract

Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. Conclusion: These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization. (HEPATOLOGY 2011;)

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/hep.24377

Cites

9 of 9 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MitoQ has been tested successfully in human diseases such as Hepatitis C induced liver disease and skin photo damage and in experimental animal models including ischemia-reperfusion, neurodegenerative diseases, diabetes, and alcohol-induced hepatosteatosis.

    “For example, Mitoquinone (MitoQ) has been tested successfully in human diseases such as Hepatitis C induced liver disease and skin photo damage as well as a number of experimental animal models including ischemia-reperfusion, neurodegenerative diseases, diabetes, and alcohol-induced hepatosteatosis [8–14].”

    From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [14]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 55

  1. [1]Lieber CS Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis Alcohol 2004 34 9 19 15670660
  2. [2]Hoek JB Pastorino JG Ethanol, oxidative stress, and cytokine-induced liver cell injury Alcohol 2002 27 63 68 12062639
  3. [3]Hoek JB Cahill A Pastorino JG Alcohol and mitochondria: a dysfunctional relationship Gastroenterology 2002 122 2049 2063 12055609 PMC1868435
  4. [4]Cahill A Cunningham CC Adachi M Ishii H Bailey SM Fromenty B Davies A Effects of alcohol and oxidative stress on liver pathology: the role of the mitochondrion Alcohol Clin Exp Res 2002 26 907 915 12068261 PMC2670542
  5. [5]Breitkopf K Nagy LE Beier JI Mueller S Weng H Dooley S Current experimental perspectives on the clinical progression of alcoholic liver disease Alcohol Clin Exp Res 2009 33 1647 1655 19645734 PMC6152826
  6. [6]Arteel G Marsano L Mendez C Bentley F McClain CJ Advances in alcoholic liver disease Best Pract Res Clin Gastroenterol 2003 17 625 647 12828959
  7. [7]Venkatraman A Shiva S Wigley A Ulasova E Chhieng D Bailey SM Darley-Usmar VM The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice Hepatology 2004 40 565 573 15349894
  8. [10]Wheeler MD Kono H Yin M Nakagami M Uesugi T Arteel GE Gabele E The role of Kupffer cell oxidant production in early ethanol-induced liver disease Free Radic Biol Med 2001 31 1544 1549 11744328
  9. [12]Lu Y Cederbaum AI CYP2E1 and oxidative liver injury by alcohol Free Radic Biol Med 2008 44 723 738 18078827 PMC2268632
  10. [13]Bailey SM A review of the role of reactive oxygen and nitrogen species in alcohol-induced mitochondrial dysfunction Free Radic Res 2003 37 585 596 12868485
  11. [14]Bailey SM Cunningham CC Contribution of mitochondria to oxidative stress associated with alcoholic liver disease Free Radic Biol Med 2002 32 11 16 11755312
  12. [15]Venkatraman A Landar A Davis AJ Chamlee L Sanderson T Kim H Page G Modification of the mitochondrial proteome in response to the stress of ethanol-dependent hepatotoxicity J Biol Chem 2004 279 22092 22101 15033988
  13. [16]Mantena SK King AL Andringa KK Landar A Darley-Usmar V Bailey SM Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease World J Gastroenterol 2007 13 4967 4973 17854139 PMC4434620
  14. [17]Sykora P Kharbanda KK Crumm SE Cahill A S-adenosyl-L-methionine co-administration prevents the ethanol-elicited dissociation of hepatic mitochondrial ribosomes in male rats Alcohol Clin Exp Res 2009 33 1 9 18828798 PMC2680437
  15. [18]Carbone DL Doorn JA Kiebler Z Petersen DR Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase Chem Res Toxicol 2005 18 1324 1331 16097806
  16. [19]Chen J Robinson NC Schenker S Frosto TA Henderson GI Formation of 4-hydroxynonenal adducts with cytochrome c oxidase in rats following short-term ethanol intake Hepatology 1999 29 1792 1798 10347122
  17. [20]Lee JH Yang ES Park JW Inactivation of NADP+-dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury J Biol Chem 2003 278 51360 51371 14551203
  18. [21]Baraona E Zeballos GA Shoichet L Mak KM Lieber CS Ethanol consumption increases nitric oxide production in rats, and its peroxynitrite-mediated toxicity is attenuated by polyenylphosphatidylcholine Alcohol Clin Exp Res 2002 26 883 889 12068258
  19. [22]King AL Swain TM Dickinson DA Lesort MJ Bailey SM Chronic ethanol consumption enhances sensitivity to Ca(2+)-mediated opening of the mitochondrial permeability transition pore and increases cyclophilin D in liver Am J Physiol Gastrointest Liver Physiol 299 G954 966 20651005 PMC2957342
  20. [23]Pastorino JG Marcineviciute A Cahill A Hoek JB Potentiation by chronic ethanol treatment of the mitochondrial permeability transition Biochem Biophys Res Commun 1999 265 405 409 10558880
  21. [24]Mantena SK Vaughn DP Andringa KK Eccleston HB King AL Abrams GA Doeller JE High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo Biochem J 2009 417 183 193 18752470 PMC2637578
  22. [26]Lieber CS S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings Alcohol 2002 27 173 177 12163146
  23. [27]Bailey SM Robinson G Pinner A Chamlee L Ulasova E Pompilius M Page GP S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver Am J Physiol Gastrointest Liver Physiol 2006 291 G857 867 16825707
  24. [28]Kono H Arteel GE Rusyn I Sies H Thurman RG Ebselen prevents early alcohol-induced liver injury in rats Free Radic Biol Med 2001 30 403 411 11182296
  25. [29]Loguercio C Federico A Oxidative stress in viral and alcoholic hepatitis Free Radic Biol Med 2003 34 1 10 12498974
  26. [30]Nath B Levin I Csak T Petrasek J Mueller C Kodys K Catalano D Hepatocyte-specific hypoxia inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice Hepatology:n/a-n/a PMC3104403 21520168
  27. [31]Bell EL Klimova TA Eisenbart J Moraes CT Murphy MP Budinger GR Chandel NS The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production J Cell Biol 2007 177 1029 1036 17562787 PMC2064363
  28. [32]Sanjuan-Pla A Cervera AM Apostolova N Garcia-Bou R Victor VM Murphy MP McCreath KJ A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1alpha FEBS Lett 2005 579 2669 2674 15862307
  29. [34]Simon MC Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization Adv Exp Med Biol 2006 588 165 170 17089888
  30. [35]Murphy MP Targeting lipophilic cations to mitochondria Biochim Biophys Acta 2008 1777 1028 1031 18439417
  31. [37]James AM Cocheme HM Smith RA Murphy MP Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools J Biol Chem 2005 280 21295 21312 15788391
  32. [38]Chacko B Reily C Srivastava A Johnson MS Ulasova E Agarwal A Zinn K Prevention of diabetic nephropathy in Ins2+/-AkitaJ mice by the mitochondria-targeted therapy Mito Q Biochem J PMC2973231 20825366
  33. [39]Supinski GS Murphy MP Callahan LA MitoQ administration prevents endotoxin-induced cardiac dysfunction Am J Physiol Regul Integr Comp Physiol 2009 297 R1095 1102 19657095 PMC2763820
  34. [41]Simon MC Coming up for air: HIF-1 and mitochondrial oxygen consumption Cell Metab 2006 3 150 151 16517402
  35. [42]Arteel GE Thurman RG Raleigh JA Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state Eur J Biochem 1998 253 743 750 9654074
  36. [43]Snow BJ Rolfe FL Lockhart MM Frampton CM O'Sullivan JD Fung V Smith RA A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease Mov Disord 25 1670 1674 20568096
  37. [44]Lieber CS DeCarli LM The feeding of alcohol in liquid diets: two decades of applications and 1982 update Alcohol Clin Exp Res 1982 6 523 531 6758624
  38. [45]Park SH Choi MS Park T Changes in the hepatic gene expression profile in a rat model of chronic ethanol treatment Food Chem Toxicol 2008 46 1378 1388 17920746
  39. [46]Arteel GE Kadiiska MB Rusyn I Bradford BU Mason RP Raleigh JA Thurman RG Oxidative stress occurs in perfused rat liver at low oxygen tension by mechanisms involving peroxynitrite Mol Pharmacol 1999 55 708 715 10101029
  40. [47]Zhou J Damdimopoulos AE Spyrou G Brune B Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia-inducible factor-1alpha J Biol Chem 2007 282 7482 7490 17220299
  41. [48]Li L Chen SH Zhang Y Yu CH Li SD Li YM Is the hypoxia-inducible factor-1 alpha mRNA expression activated by ethanol-induced injury, the mechanism underlying alcoholic liver disease? Hepatobiliary Pancreat Dis Int 2006 5 560 563 17085342
  42. [49]French SW The role of hypoxia in the pathogenesis of alcoholic liver disease Hepatol Res 2004 29 69 74 15163427
  43. [50]Tomita K Tamiya G Ando S Kitamura N Koizumi H Kato S Horie Y AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats Alcohol Clin Exp Res 2005 29 240S 245S 16385230
  44. [51]Shiva S Oh JY Landar AL Ulasova E Venkatraman A Bailey SM Darley-Usmar VM Nitroxia: the pathological consequence of dysfunction in the nitric oxide-cytochrome c oxidase signaling pathway Free Radic Biol Med 2005 38 297 306 15629859
  45. [52]Cunningham CC Bailey SM Ethanol consumption and liver mitochondria function Biol Signals Recept 2001 10 271 282 11351133
  46. [53]Smith RA Murphy MP Animal and human studies with the mitochondria-targeted antioxidant MitoQ Ann N Y Acad Sci 1201 96 103 20649545
  47. [55]Chandran K Aggarwal D Migrino RQ Joseph J McAllister D Konorev EA Antholine WE Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q Biophys J 2009 96 1388 1398 19217856 PMC2717244
  48. [56]James AM Sharpley MS Manas AR Frerman FE Hirst J Smith RA Murphy MP Interaction of the mitochondria-targeted antioxidant MitoQ with phospholipid bilayers and ubiquinone oxidoreductases J Biol Chem 2007 282 14708 14718 17369262
  49. [57]Seki S Kitada T Sakaguchi H Nakatani K Wakasa K Pathological significance of oxidative cellular damage in human alcoholic liver disease Histopathology 2003 42 365 371 12653948
  50. [58]Cocheme HM Kelso GF James AM Ross MF Trnka J Mahendiran T Asin-Cayuela J Mitochondrial targeting of quinones: therapeutic implications Mitochondrion 2007 7 Suppl S94 102 17449335
  51. [59]Kurose I Higuchi H Kato S Miura S Watanabe N Kamegaya Y Tomita K Oxidative stress on mitochondria and cell membrane of cultured rat hepatocytes and perfused liver exposed to ethanol Gastroenterology 1997 112 1331 1343 9098019
  52. [60]Lowes DA Thottakam BM Webster NR Murphy MP Galley HF The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis Free Radic Biol Med 2008 45 1559 1565 18845241
  53. [61]Arteel GE Raleigh JA Bradford BU Thurman RG Acute alcohol produces hypoxia directly in rat liver tissue in vivo: role of Kupffer cells Am J Physiol 1996 271 G494 500 8843775
  54. [62]Fong GH Takeda K Role and regulation of prolyl hydroxylase domain proteins Cell Death Differ 2008 15 635 641 18259202
  55. [64]Zeng T Xie KQ Ethanol and liver: recent advances in the mechanisms of ethanol-induced hepatosteatosis Arch Toxicol 2009 19588123

Cited by

Sorted by citations

Authors
Chacko, B. K., Srivastava, A., Johnson, M. S., Benavides, G. A., Chang, M. J., Ye, Y., Jhala, N., Murphy, M. P., Kalyanaraman, B., & Darley-Usmar, V. M.
Affiliations
  • University of Alabama at Birmingham (US)
  • MRC Mitochondrial Biology Unit (GB)
  • Medical College of Wisconsin (US)
Corresponding author
Darley-Usmar, Victor M.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2011-07
Volume
54
Issue
1
Pages
153-163
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.24377
PMC
PMC3125473
OpenAlex
W2043429649
Cited by
122
References
9
Citations by year
2026: 3 · 2025: 9 · 2024: 12 · 2023: 4 · 2022: 8 · 2021: 9 · 2020: 5 · 2019: 4 · 2018: 10 · 2017: 10 · 2016: 3 · 2015: 7 · 2014: 14 · 2013: 12 · 2012: 9
FWCI
8.06
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1 (tdm, 1523 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (R01AA013395, AA013395)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
MitoQ, alcoholic liver disease, hepatic steatosis, oxidative stress, nitrosative stress, nitrotyrosine, 4-hydroxynonenal, HIF-1α, mitochondrial respiratory chain, reactive oxygen species, reactive nitrogen species, CYP2E1, hepatocyte ballooning, lipid accumulation
MeSH terms
Ethanol, Animals, Antioxidants, Disease Models, Animal, Dose-Response Relationship, Drug, Electron Transport, Fatty Liver, Liver, Male, Mitochondria, Liver, Organophosphorus Compounds, Ubiquinone, Rats, Sprague-Dawley, Reactive Oxygen Species, Cytochrome P-450 CYP2E1, Lipid Metabolism, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, AMP-Activated Protein Kinases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review