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Cited by 123Mitochondrial Function and PathologyAlcohol Consumption and Health EffectsDrug-Induced Hepatotoxicity and Protection

Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications

Open access
Song, Byoung-Joon, Akbar, Mohammed, Abdelmegeed, Mohamed A., Byun, Kyunghee, Lee, Bonghee, Yoon, Seung Kew, Hardwick, James P.·2014·Redox Biology
DOI 10.1016/j.redox.2014.10.004PMC PMC4297931
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Abstract

Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that five major post-translational modifications (oxidation, nitration, phosphorylation, acetylation, and electrophilic adduct formation) of mitochondrial proteins drive mitochondrial dysfunction, fat accumulation, inflammation, and tissue injury in alcoholic and nonalcoholic fatty liver disease and acute drug-induced liver injury. It highlights the ethanol-inducible CYP2E1 as a recurring contributor and discusses mitochondria-targeted antioxidants as translational opportunities.

Key findings

  • Mass-spectral analyses cited in the review identified more than 87 mitochondrial and 60 cytosolic proteins oxidatively modified in alcohol-exposed rodents, and more than 70 mitochondrial and 30 cytosolic proteins nitrated in acetaminophen (APAP)-exposed mice; the authors note these may represent a small fraction of the estimated 1100–1400 total mitochondrial proteins.
  • Oxidative/S-nitrosylation modification of active-site Cys residues inactivates key enzymes including ALDH2, thiolase, Prx1, and NADP+-ICDH; ALDH2 activity suppressed in ethanol-exposed rats was fully restored by DTT treatment.
  • In APAP-treated mice, N-acetyl-cysteine completely protected the liver from necrotic injury and prevented Tyr nitration and inactivation of five selected enzymes (SOD2, Gpx, ATP synthase, ALDH2, thiolase).
  • Acetylation studies identified 91 acetylated mitochondrial proteins in alcohol-exposed mice (including ALDH2, ATP synthase, Gpx, thiolase); approximately 20% of mitochondrial proteins and 44% of NAD+-dependent mitochondrial dehydrogenases are acetylated under physiological conditions.
  • In 50 alcoholic cirrhosis patients, average MDA- and HNE-protein adduct levels were significantly higher than in nonalcoholic cirrhosis or healthy individuals, while ACR- and MGO-adducts did not differ; MDA/HNE adducts were also higher in 51 alcoholic patients with advanced fibrosis/cirrhosis than in 23 fatty liver or 30 healthy controls.

Methods

  • Narrative review of the literature on five major PTMs of mitochondrial proteins in experimental models of alcoholic fatty liver disease (AFLD), nonalcoholic fatty liver disease (NAFLD), and acute liver injury, with emphasis on CYP2E1.
  • Synthesizes cited experimental evidence including rodent and cell-culture models (e.g., binge/chronic alcohol, high-fat diets, APAP, MDMA, ischemia-reperfusion, LPS), mass-spectrometry-based proteomic identification of modified proteins, and human patient adduct measurements.
  • Concludes with a discussion of natural and synthetic antioxidants and mitochondria-targeted compounds (SS-peptides, MitoQ, Mito-CP).

Limitations

  • Stated by the paper: it is difficult to clearly demonstrate the deleterious effect of each single PTM or which PTM plays a critical role, since many proteins may be modified by multiple PTMs simultaneously; identifying modified amino acids and their roles in activity changes is challenging; it remains unknown which low-abundance proteins are modified; other PTM types (methylation, glycosylation, sumoylation, ubiquitination) and extra-hepatic tissues (brain, heart, pancreas, adipose, intestine) need further study.
  • Stated by the paper: technical limitations in identification and purification of oxidized proteins and detection methods, especially for low-abundance proteins, mean the actual number of oxidized proteins could be significantly higher than reported.
  • Evident from the text: as a review, it presents no new primary data, and several cited mechanistic conclusions (e.g., that HNE-modified proteins are functionally suppressed) are described as assumptions rather than measured outcomes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.redox.2014.10.004

Cites

246 of 246 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 132 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Similar numbers of oxidatively-modified mitochondrial proteins were identified by mass-spectral analysis in mice with I/R injury and rats exposed to MDMA.

    “Similar numbers of oxidatively-modified mitochondrial proteins were also identified by mass-spectral analysis in mice with I/R injury [38] and rats exposed to 3,4-methylenedioxymethamphetamine (MDMA) [39].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source

      Not checked in the free run.

    • cites [39] Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics source

      Not checked in the free run.

  • Findingcitation

    The rates of protein oxidation in CYP2E1-containing E47-HepG2 hepatoma cells exhibited a dose- and time-dependent pattern in response to alcohol as well as the presence of CYP2E1.

    “The rates of protein oxidation in CYP2E1-containing E47-HepG2 hepatoma cells [36] exhibited a dose- and time- dependent pattern in response to alcohol as well as the presence of CYP2E1 [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Suh, 2004, Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver, Proteomics source

      Not checked in the free run.

  • Findingcitation

    Mass-spectral analysis revealed that more than 87 mitochondrial and 60 cytosolic proteins were oxidatively-modified in alcohol-exposed rodents.

    “In fact, mass-spectral analysis revealed that more than 87 mitochondrial and 60 cytosolic proteins were oxidatively-modified in alcohol-exposed rodents [34], [35].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.) source

      Not checked in the free run.

    • cites [35] Kim, 2006, Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells, Proteomics source

      Not checked in the free run.

  • Findingown data

    Treatment with NAC completely protected the liver from APAP-induced necrotic injury measured by increased serum transaminase activities and liver histology.

    “Treatment with NAC completely protected the liver from the APAP-induced necrotic injury measured by increased serum transaminase activities and liver histology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

      Not checked in the free run.

  • Findingown data

    NAC ameliorated the inactivation of the five critical enzymes via preventing Tyr nitration.

    “Furthermore, NAC ameliorated the inactivation of the five critical enzymes via preventing Tyr nitration, as evidenced by immunoprecipitation with a specific antibody to each protein followed by immunoblot with anti-3-NT antibody.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

      Not checked in the free run.

  • May combine two claims. 24
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Findingcitation

    Oxidative modification and inactivation of ALDH2 were also observed after exposure to MDMA or I/R injury, resulting in the accumulation of lipid peroxidation products, which are metabolized by ALDH2.

    “Oxidative modification and inactivation of ALDH2 were also observed after exposure to MDMA [39] or I/R injury [38], resulting in the accumulation of lipid peroxidation products, which are metabolized by ALDH2 [46].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics source

      Not checked in the free run.

    • cites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source

      Not checked in the free run.

    • cites [46] Hartley, 1995, The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase, Archives of Biochemistry and Biophysics source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Mass-spectral analysis confirmed that Cys305 and Cys387 of NADP+-ICDH were S-nitrosylated, resulting in its inactivation in alcohol-exposed animals.

    “Mass-spectral analysis confirmed that Cys305 and Cys387 of NADP+-ICDH were S-nitrosylated, resulting in its inactivation in alcohol-exposed animals [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Lee, 2003, Inactivation of NADP+-dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury, Journal of Biological Chemistry source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The identified nitrated proteins are involved in cellular energy production, fat metabolism, intermediary metabolism, urea cycle, chaperone activity, and anti-oxidant defense.

    “The identified nitrated proteins are involved in cellular energy production, fat metabolism, intermediary metabolism, urea cycle, chaperone activity, and anti-oxidant defense.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    AA-AGE but not N-ethyllysine (NEL) caused apoptosis of rat hepatocytes, suggesting an important role of AA-AGE in alcohol-induced hepatotoxicity and fatty liver injury.

    “Furthermore, AA-AGE but not N-ethyllysine (NEL) caused apoptosis of rat hepatocytes, suggesting an important role of AA-AGE in alcohol-induced hepatotoxicity and fatty liver injury [193].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Hayashi, 2013, Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease, PloS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress.

    “It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although increased nitroxidative stress can oxidatively damage mitochondrial DNA and lipids, the majority of insults can also take place at the protein levels through different forms of post-translational modification (PTM).

    “Although increased nitroxidative stress can oxidatively damage mitochondrial DNA and lipids, the majority of insults can also take place at the protein levels through different forms of post-translational modification (PTM) [26], [27].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source

      Not checked in the free run.

    • cites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated.

    “Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Continued mitochondrial dysfunction with increased oxidative stress sensitizes hepatocytes to subsequent necrosis and/or apoptosis, which likely leads to activation of Kupffer cells and recruitment of infiltrating immune cells with elevated hepatic inflammation and pro-inflammatory cytokines/chemokines.

    “Continued mitochondrial dysfunction with increased oxidative stress also sensitizes the hepatocytes to subsequent necrosis and/or apoptosis of hepatocytes, which likely lead to activation of resident liver macrophage (i.e., Kupffer cells) and recruitment of infiltrating immune cells into the liver with elevated levels of hepatic inflammation (steatohepatitis) and pro-inflammatory cytokines/chemok”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Purohit, 2009, Molecular mechanisms of alcoholic fatty liver, Alcoholism, Clinical and Experimental Research source

      Not checked in the free run.

    • cites [14] Gao, 2011, Alcoholic liver disease: pathogenesis and new therapeutic targets, Gastroenterology source

      Not checked in the free run.

    • cites [15] Barnes, 2014, Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1, Redox Biology source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal physiological functions.

    “Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Hepatic stellate cells can be activated and transformed into myofibroblast-like cells, producing pro-fibrotic cytokines, leading to hepatic fibrosis/cirrhosis and cancer.

    “Consequently, hepatic stellate cells can be activated and transformed into myofibroblast-like cells, producing pro-fibrotic cytokines such as transforming growth factor-beta and platelet derived growth factor, leading to hepatic fibrosis/cirrhosis and cancer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Many toxic agents such as alcohol, APAP and LPS can induce iNOS, which produces greater amounts of NO, likely leading to nitrosative/nitrative stress.

    “However, many toxic agents such as alcohol, APAP and LPS can induce iNOS, which produces greater amounts of NO, likely leading to nitrosative/nitrative stress [27], [75], [76], [77].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source

      Not checked in the free run.

    • cites [75] Calcerrada, 2011, Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications, Current Pharmaceutical Design source

      Not checked in the free run.

    • cites [76] Brenner, 2013, Decoding cell death signals in liver inflammation, Journal of Hepatology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APAP was first shown to induce and promote mitochondrial protein nitration and peroxynitrite can cause mitochondrial DNA damage.

    “APAP was first shown to induce and promote mitochondrial protein nitration and that peroxynitrite can cause mitochondrial DNA damage by Cover et al. [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Cover, 2005, Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity, Journal of Pharmacology and Experimental Therapeutics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO can interact with ROS to produce peroxynitrite, which can nitrate Tyr residues to generate 3-nitroTyr or S-nitrosylate Cys residues of many proteins.

    “In this case, NO can interact with ROS to produce a potently toxic peroxynitrite, which can nitrate Tyr residues to generate 3-nitroTyr (3-NT) or S-nitrosylate Cys residues of many proteins [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Radi, 1991, Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide, Journal of Biological Chemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK serves as a key sensor and/or regulator of metabolic syndrome and many cellular processes.

    “Regulatory mechanism of AMP-dependent protein kinase (AMPK) by alcohol and other non-alcoholic substances, including high fat diet has become an important research topic, since AMPK serves as a key sensor and/regulator of metabolic syndrome and many cellular processes [136].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Hardie, 2014, AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels, Annual Review of Nutrition source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pretreatment with a specific inhibitor of CYP2E1 blocked metabolic activation of some hepatotoxic agents, which are CYP2E1 substrates, and prevented JNK activation.

    “Pretreatment with a specific inhibitor of CYP2E1 blocked metabolic activation of some hepatotoxic agents, which are CYP2E1 substrates [110], [111], [112], [113], [114], [115], [116], [117], [118], and prevented JNK activation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [110] Lee, 2005, Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes, European Journal of Pharmacology source

      Not checked in the free run.

    • cites [111] Yang, 2012, Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver, Free Radical Biology and Medicine source

      Not checked in the free run.

    • cites [112] Bae, 2001, Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway, Molecular Pharmacology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Suppressed ATP synthase activity would lead to decreased ATP production, interfering with vital cell functions and ultimately causing necrosis.

    “Suppressed ATP synthase activity would lead to decreased ATP production, interfering with vital cell functions and ultimately causing necrosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitration can also increase the activity of some proteins such as GST, HSP90, and PP2, or exert no effects at all as reported with transferrin.

    “However, it would be prudent to double-check the function of each nitrated protein, since nitration can also increase the activity of some proteins such as glutathions S-transferase (GST), heat shock protein 90 (HSP90), and protein phosphatase type 2 [PP2], or exert no effects at all as reported with transferrin [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Suppressed ALDH2 would lead to accumulation of toxic, reactive aldehydes and lipid peroxidation.

    “Furthermore, suppressed ALDH2 would lead to the accumulation of toxic, reactive aldehydes and lipid peroxidation, as previously mentioned in the oxidation section [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK can be activated by hydrogen peroxide and mitochondria-derived ROS since its activation can be prevented by pretreatment with antioxidants such as NAC or GSH-ethyl ester.

    “For instance, AMPK can be activated by hydrogen peroxide and mitochondria-derived ROS since its activation can be prevented by pretreatment with antioxidants such as NAC or GSH-ethyl ester [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Sid, 2013, Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease, Biochemical Pharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sustained JNK activation leads to phosphorylation at Ser-46 of sirtuin 1, followed by ubiquitin-dependent degradation, contributing to fat accumulation in obese mice.

    “A recent study also showed that sustained JNK activation led to phosphorylation at Ser-46 of sirtuin 1, NAD+-dependent deacetylase in cytosol (described later), followed by ubiquitin-dependent degradation, contributing to fat accumulation in obese mice [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Gao, 2011, Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity, Journal of Biological Chemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excessive alcohol intake and many potentially toxic compounds can suppress low Km mitochondrial ALDH2 activity in rodents and humans through various PTMs of the active site Cys residue and other redox-sensitive amino acids, resulting in the accumulation of toxic acetaldehyde and other lipid aldehydes.

    “It is well-established that excessive alcohol intake and many potentially toxic compounds can suppress low Km mitochondrial ALDH2 activity in rodents and humans through various PTMs of the active site Cys residue and other redox-sensitive amino acids, as reviewed [26], [27], [42], resulting in the accumulation of toxic acetaldehyde and other lipid aldehydes.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source

      Not checked in the free run.

    • cites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source

      Not checked in the free run.

    • cites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of acetylated proteins can be significantly increased in experimental models of pathological conditions or following exposure to hepatotoxic agents, possibly resulting from redox-mediated suppression of deacetylases.

    “The number of acetylated proteins can be significantly increased in experimental models of pathological conditions or following exposure to hepatotoxic agents, possibly resulting from redox-mediated suppression of deacetylases, as shown in alcohol-exposed [142], [143], [144], [145] or high-fat exposed rodents [146], [147], [148].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [142] You, 2008, Involvement of mammalian sirtuin 1 in the action of ethanol in the liver, American Journal of Physiology: Gastrointestinal and Liver Physiology

      Not checked in the free run.

    • cites [143] Lieber, 2008, Effect of chronic alcohol consumption on hepatic SIRT1 and PGC-1alpha in rats, Biochemical and Biophysical Research Communications source

      Not checked in the free run.

    • cites [144] Picklo, 2008, Ethanol intoxication increases hepatic N-lysyl protein acetylation, Biochemical and Biophysical Research Communications source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cyp2e1-null mice are resistant to alcohol-mediated gut leakiness, whereas wild-type mice show it.

    “In addition, Cyp2e1-null mice were resistant to alcohol-mediated gut leakiness, which was clearly observed in the corresponding wild-type mice [238].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [238] Abdelmegeed, 2013, CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis, Free Radical Biology and Medicine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 20% of mitochondrial proteins and 44% of NAD+-dependent mitochondrial dehydrogenases are acetylated under physiological conditions.

    “A large scale proteomics study revealed that approximately 20% of mitochondrial proteins and 44% of NAD+-dependent mitochondrial dehydrogenases are acetylated under physiological conditions [141].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Kim, 2006, Substrate and functional diversity of lysine acetylation revealed by a proteomics survey, Molecular Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated levels of cross-linked AGEs in many tissues can up-regulate the expression of the receptor for AGEs (RAGE), which activates NADPH oxidase, leading to increased oxidative stress, insulin resistance, and inflammation with disruption of normal cell signaling pathways.

    “Elevated levels of cross-linked AGEs in many tissues can up-regulate the expression of the receptor for AGEs (RAGE), which activates NADPH oxidase, leading to increased oxidative stress, insulin resistance, and inflammation with disruption of normal cell signaling pathways.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Many proteins can be modified by multiple PTMs simultaneously.

    “Although several PTMs in many mitochondrial proteins were identified in different disease states or under increased nitroxidative stress, it is quite possible that many proteins can be modified by multiple PTMs simultaneously.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Activation of sirtuins by small molecule polyphenols including resveratrol and green tea extracts can reduce the number of acetylated proteins, including PGC-1α, which contributes to increased fat oxidation and insulin sensitivity with improved outcome against metabolic syndrome.

    “In contrast, activation of sirtuins by small molecule polyphenols including resveratrol [156] and green tea extracts [157] can reduce the number of acetylated proteins, including PGC-1α, which contributes to increased fat oxidation and insulin sensitivity with improved outcome against metabolic syndrome.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Yang, 2014, Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation, Metabolism: Clinical and Experimental source

      Not checked in the free run.

    • cites [157] Wang, 2014, Novel insights of dietary polyphenols and obesity, Journal of Nutritional Biochemistry source

      Not checked in the free run.

27 of 27

  • The paper relies on this without support.

    The experimental models used in the cited and own studies are adequate to infer mechanisms of human alcoholic/nonalcoholic fatty liver disease and acute liver injury.

    “We used APAP as a well-established model agent for acute drug-induced liver injury (DILI) to study the functional role of nitrated mitochondrial proteins and the mechanisms of mitochondrial dysfunction and hepatotoxicity.”

  • The authors state this as an assumption.

    The functional activities of some of the HNE-modified mitochondrial proteins could be suppressed.

    “Although the activities of each HNE-modified protein were not determined in this study, it is reasonable to assume that the functional activities of some of the modified proteins could be suppressed.”

  • The paper relies on this without support.

    Treatment with the antioxidant NAC or the CYP2E1 inhibitor chlormethiazole significantly prevents gut leakiness and liver injury in binge alcohol-induced gut leakiness.

    “since treatment with an antioxidant NAC or a CYP2E1 inhibitor chlormethiazole significantly prevented gut leakiness and liver injury.”

  • The paper relies on this without support.

    The functional roles of redox-regulated PTMs on many intestinal proteins are still poorly understood.

    “Despite numerous reports on gut leakiness caused by alcohol and fructose [232], [233], [234], [235], [236], [237], [238], [239], [240], [241], [242], the functional roles of redox-regulated PTMs on many intestinal proteins are still poorly understood.”
4 of 4

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?

  • AGEs stimulate mitochondrial ROS production and JNK and NADPH oxidase activity to induce mitochondrial dysfunction and oxidative stress.

    “AGEs also stimulate mitochondrial ROS production and c-Jun N-terminal protein kinase (JNK) and NADPH oxidase activity to induce mitochondrial dysfunction and oxidative stress51–53.”

    From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [53]

  • Dietary AGEs disrupt and downregulate SIRT1 expression, resulting in acetylation and inactivation of PGC1α.

    “Dietary AGEs have been found to disrupt and downregulate sirtuin1 (SIRT1) expression, resulting in the acetylation and inactivation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), a master regulator of mitochondrial metabolism.”

    From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [53]

  • Acetaldehyde in the brain alters DNA integrity and neuronal viability; it can form AA-DNA adducts in the brain and peripheral blood leukocytes of people with AUD since ethanol, acetaldehyde, and lipid aldehydes such as MDA and 4-HNE can inhibit DNA repair enzymes; dual mechanisms of elevated AA-DNA adducts and suppressed DNA repair may contribute to genetic instability and DNA mutations, promoting

    “The presence of acetaldehyde in the brain also alters DNA integrity and neuronal viability.”

    From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [53]

  • Excessive alcohol exposure increases oxidative stress and levels of reactive acetaldehyde and lipid aldehydes with simultaneous decrease in defensive molecules and detoxification enzymes including GSH and ALDH2, leading to accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver.

    “Excessive alcohol exposure increases oxidative stress and the levels of reactive acetaldehyde and lipid aldehydes with a simultaneous decrease in defensive molecules and detoxification enzymes, including GSH and ALDH253,172,177.”

    From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [53]

  • Naturally occurring CYP2E1 inhibitors and synthetic compounds can prevent alcohol-induced oxidative stress and the formation of various adducts, including AA adducts and AA-MAA adducts.

    “can prevent alcohol-induced oxidative stress and the formation of various adducts, including AA adducts137 and AA-MAA adducts53,285”

    From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [53]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • ALDH2 restoration is attributed to DDT instead of DTT

    Minor

    The treatment group is described as receiving dithiothreitol (DTT), but the subsequent sentence attributes restoration of ALDH2 activity to DDT treatment. These name different treatments.

1 of 1

Cites

2 retracted

Flagged first, then by citations

5 of the 251 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P.
Affiliations
  • National Institutes of Health (US)
  • Gachon University (KR)
  • Catholic University of Korea (KR)
  • Northeast Ohio Medical University (US)
Corresponding author
Song, Byoung-Joon
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2014
Volume
3
Pages
109-123
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2014.10.004
PMC
PMC4297931
OpenAlex
W2044394582
Semantic Scholar
9ac8ad35c9150429a0fcab4a6ea86e3c3e4f9b88
Cited by
123
References
251
Citations by year
2026: 5 · 2025: 11 · 2024: 14 · 2023: 13 · 2022: 13 · 2021: 6 · 2020: 6 · 2019: 9 · 2018: 13 · 2017: 14 · 2016: 11 · 2015: 8
FWCI
4.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Alcohol Abuse and Alcoholism
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
mitochondrial dysfunction, post-translational modification, oxidative stress, nitrosative stress, alcohol-induced liver injury, non-alcoholic fatty liver disease, high-fat diet, CYP2E1, protein oxidation, protein nitration, protein phosphorylation, protein acetylation, advanced glycation end products, antioxidants, tissue damage
MeSH terms
Ethanol, Animals, Antioxidants, Humans, Liver Diseases, Mitochondria, Oxidation-Reduction, Protein Processing, Post-Translational, Oxidative Stress, Translational Research, Biomedical, Diet, High-Fat

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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 ›

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