The DOI matches its Crossref record; 246 of the 251 references it cites were found in a registry or an index; none of the 132 sources its claims cite is checked for support yet.
Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications
Open accessAbstract
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.
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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.
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In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Oxidation of mitochondrial proteins
What the sources say
- Not checked yetcites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source
- Not checked yetcites [39] Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Oxidation of mitochondrial proteins
What the sources say
- Not checked yetcites [37] Suh, 2004, Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver, Proteomics source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“In fact, mass-spectral analysis revealed that more than 87 mitochondrial and 60 cytosolic proteins were oxidatively-modified in alcohol-exposed rodents [34], [35].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Oxidation of mitochondrial proteins
What the sources say
- Not checked yetcites [34] Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.) source
- Not checked yetcites [35] Kim, 2006, Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells, Proteomics source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Treatment with NAC completely protected the liver from the APAP-induced necrotic injury measured by increased serum transaminase activities and liver histology.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Furthermore, oxidative modification of the active site Cys residue of peroxiredoxin 1 (Prx1) and inactivation was observed in alcohol-exposed mice [47].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Oxidation of mitochondrial proteins
What the sources say
- Not checked yetcites [47] Bae, 2011, Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol-induced oxidative injury in mouse liver, Hepatology (Baltimore, Md.) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“In fact, after immunoaffinity purification followed by mass-spectral analysis, we demonstrated that more than 70 mitochondrial proteins and 30 cytosolic proteins were nitrated in APAP-exposed mice [94].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Our results showed that pro-apoptotic Bax in the cytosol can be phosphorylated (activated) by p-JNK and/or p-p38K, resulting in its conformational change with exposure of the C-terminal membrane domain.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Phosphorylation of mitochondrial proteins
What the sources say
- Not checked yetcites [129] Kim, 2006, JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells, Journal of Biological Chemistry source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Our results revealed that Thr167 of Bax was phosphorylated before it was translocated to mitochondria to stimulate mitochondria-dependent apoptosis [129].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Phosphorylation of mitochondrial proteins
What the sources say
- Not checked yetcites [129] Kim, 2006, JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells, Journal of Biological Chemistry source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“By using immunoprecipitation with anti-Ac-Lys antibody followed by mass spectral analysis, 91 acetylated mitochondrial proteins were recently identified in alcohol exposed mice [152].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Acetylation of mitochondrial proteins
What the sources say
- Not checked yetcites [152] Fritz, 2012, Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice, Journal of Proteome Research source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 24
- Probably not a substantial claim. 3
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Oxidation of mitochondrial proteins
What the sources say
- Not checked yetcites [39] Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics source
- Not checked yetcites [38] Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology source
- Not checked yetcites [46] Hartley, 1995, The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase, Archives of Biochemistry and Biophysics source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Mass-spectral analysis confirmed that Cys305 and Cys387 of NADP+-ICDH were S-nitrosylated, resulting in its inactivation in alcohol-exposed animals [53].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Oxidation of mitochondrial proteins
What the sources say
- Not checked yetcites [53] Lee, 2003, Inactivation of NADP+-dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury, Journal of Biological Chemistry source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The identified nitrated proteins are involved in cellular energy production, fat metabolism, intermediary metabolism, urea cycle, chaperone activity, and anti-oxidant defense.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [94] Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Electrophilic adduct formation of mitochondrial proteins
What the sources say
- Not checked yetcites [193] Hayashi, 2013, Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease, PloS One source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Introduction
What the sources say
- Not checked yetcites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source
- Not checked yetcites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Introduction
What the sources say
- Not checked yetcites [13] Purohit, 2009, Molecular mechanisms of alcoholic fatty liver, Alcoholism, Clinical and Experimental Research source
- Not checked yetcites [14] Gao, 2011, Alcoholic liver disease: pathogenesis and new therapeutic targets, Gastroenterology source
- Not checked yetcites [15] Barnes, 2014, Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1, Redox Biology source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Introduction
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source
- Not checked yetcites [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 yetcites [76] Brenner, 2013, Decoding cell death signals in liver inflammation, Journal of Hepatology source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“APAP was first shown to induce and promote mitochondrial protein nitration and that peroxynitrite can cause mitochondrial DNA damage by Cover et al. [18].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [18] Cover, 2005, Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity, Journal of Pharmacology and Experimental Therapeutics source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [77] Radi, 1991, Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide, Journal of Biological Chemistry source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Phosphorylation of mitochondrial proteins
What the sources say
- Not checked yetcites [136] Hardie, 2014, AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels, Annual Review of Nutrition source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Phosphorylation of mitochondrial proteins
What the sources say
- Not checked yetcites [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 yetcites [111] Yang, 2012, Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver, Free Radical Biology and Medicine source
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Suppressed ATP synthase activity would lead to decreased ATP production, interfering with vital cell functions and ultimately causing necrosis.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Furthermore, suppressed ALDH2 would lead to the accumulation of toxic, reactive aldehydes and lipid peroxidation, as previously mentioned in the oxidation section [42].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Nitration of many mitochondrial proteins
What the sources say
- Not checked yetcites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Phosphorylation of mitochondrial proteins
What the sources say
- Not checked yetcites [101] Sid, 2013, Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease, Biochemical Pharmacology source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Phosphorylation of mitochondrial proteins
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Electrophilic adduct formation of mitochondrial proteins
What the sources say
- Not checked yetcites [26] Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity source
- Not checked yetcites [27] Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity source
- Not checked yetcites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Acetylation of mitochondrial proteins
What the sources say
- Not checked yetcites [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 yetcites [143] Lieber, 2008, Effect of chronic alcohol consumption on hepatic SIRT1 and PGC-1alpha in rats, Biochemical and Biophysical Research Communications source
- Not checked yetcites [144] Picklo, 2008, Ethanol intoxication increases hepatic N-lysyl protein acetylation, Biochemical and Biophysical Research Communications source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In addition, Cyp2e1-null mice were resistant to alcohol-mediated gut leakiness, which was clearly observed in the corresponding wild-type mice [238].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Conclusion and future research opportunities
What the sources say
- Not checked yetcites [238] Abdelmegeed, 2013, CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis, Free Radical Biology and Medicine source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Acetylation of mitochondrial proteins
What the sources say
- Not checked yetcites [141] Kim, 2006, Substrate and functional diversity of lysine acetylation revealed by a proteomics survey, Molecular Cell source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Electrophilic adduct formation of mitochondrial proteins
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Conclusion and future research opportunities
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications > Post-translational modifications of mitochondrial proteins > Acetylation of mitochondrial proteins
What the sources say
- Not checked yetcites [156] Yang, 2014, Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation, Metabolism: Clinical and Experimental source
- Not checked yetcites [157] Wang, 2014, Novel insights of dietary polyphenols and obesity, Journal of Nutritional Biochemistry source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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?
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
MinorThe treatment group is described as receiving dithiothreitol (DTT), but the subsequent sentence attributes restoration of ALDH2 activity to DDT treatment. These name different treatments.
“Furthermore, the significantly decreased ALDH2 activity in ethanol-exposed rats was fully restored by DDT treatment [34].”
“dithiothreitol (DTT)-treated mitochondria from alcohol-exposed rats”
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BackgroundMolecular Mechanisms of Alcoholic Fatty Liver
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“For instance, NF-κB, a critical transcription factor in inflammation and innate immune regulation, can be activated by alcohol [56] and other toxic agents such as lipopolysaccharide (LPS) [57].”
BackgroundInfluentialLactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice
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“In fact, acute exposure to many hepatotoxic agents including alcohol [110,111], APAP [112–116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”
BackgroundAMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels
Hardie, D. G. (2014) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071812-161148 · Cited by 281 · cited 1×
“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].”
BackgroundAlbano, E., Clot, P., Morimoto, M. S. S., Tomasi, A., Ingelman‐Sundberg, M., & French, S. W. (1996) · Hepatology · doi:10.1002/hep.510230121 · Cited by 277 · cited 2×
“droxyethyl-adduct [203,204] seem uniquely observed in AFLD.”
Central role of mitochondria in drug-induced liver injury
Pessayre, D., Fromenty, B., Berson, A., Robin, M.-A., Lettéron, P., Moreau, R., & Mansouri, A. (2012) · Drug Metabolism Reviews · doi:10.3109/03602532.2011.604086 · Cited by 277 · cited 5×
“Furthermore, these protein adducts can serve as a neo-antigen of hapten–carrier conjugate proteins to activate immune responses and to facilitate infiltration of neutrophils into the liver to promote inflammation [18–21,24,166–168].”
BackgroundInfluentialMelov, S., Doctrow, S. R., Schneider, J. A., Haberson, J., Patel, M., Coskun, P. E., Huffman, K. D., Wallace, D. C., & Malfroy, B. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-21-08348.2001 · Cited by 277 · cited 1×
“Similarly, the analogs of SOD-catalase mimetics also showed beneficial effects on many tissues including the liver and brain [221].”
BackgroundRegulation of protein function and signaling by reversible cysteine S-nitrosylation
Gould, N., Doulias, P.-T., Tenopoulou, M., Raju, K., & Ischiropoulos, H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.460261 · Cited by 274 · cited 1×
“For instance, reversible oxidation of Cys residues of mitochondrial NADH-dependent ubiquinone oxidoreductase (complex I), ALDH2, and Prx3 seem to be protective, despite temporary inactivation, against further tissue damage from irreversible hyper-oxidation of Cys to Cys-sulfinic acid (Cys-SO2) and Cys-sulfonic acid (C…”
BackgroundKnight, T. R., Ho, Y.-S., Farhood, A. I., & Jaeschke, H. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.038968 · Cited by 274
Fromenty, B., & Pessayre, D. (1997) · Journal of Hepatology · doi:10.1016/s0168-8278(97)80496-5 · Cited by 268
Yokoyama, A. (2001) · Carcinogenesis · doi:10.1093/carcin/22.3.433 · Cited by 266 · cited 1×
“…proper counter-balance by various cellular anti-oxidants, the persistent imbalance in cellular redox states result in decreased levels of mitochondrial antioxidants including mitochondrial glutathione (mtGSH), which serves as a critical determinant between toxic damage and cellular protection [30].”
BackgroundHigh fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo
Mantena, S. K., Vaughn, D. P., Andringa, K. K., Eccleston, H. B., King, A. L., Abrams, G. A., Doeller, J. E., Kraus, D. W., Darley-Usmar, V. M., & Bailey, S. M. (2009) · Biochemical Journal · doi:10.1042/bj20080868 · Cited by 265
Nadolski, M. J., & Linder, M. E. (2007) · FEBS Journal · doi:10.1111/j.1742-4658.2007.06056.x · Cited by 254
Mechanisms of acetaminophen-induced cell death in primary human hepatocytes
Xie, Y., McGill, M. R., Dorko, K., Kumer, S. C., Schmitt, T. M., Forster, J., & Jaeschke, H. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2014.05.010 · Cited by 250 · cited 1×
“In addition, activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP [115,116,130,131].”
BackgroundMolecular chaperones and proteostasis regulation during redox imbalance
Niforou, K., Cheimonidou, C., & Trougakos, I. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.01.017 · Cited by 250
Abdelmegeed, M. A., Banerjee, A., Yoo, S.-H., Jang, S., Gonzalez, F. J., & Song, B. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.05.019 · Cited by 247 · cited 1×
“We also believe similar types of lipid peroxide adducts present in the liver of high-fat exposed rodents (and humans), due to the elevated levels of oxidative stress and lipid peroxides including 4-HNE [185], as comparable to the alcoholic fatty liver [170–172].”
BackgroundSelf-citationSpecific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis
Caballero, F., Fernández, A., Matías, N., Martínez-Gili, L., Fucho, R., Elena, M., Caballería, J., Morales, A., Fernández-Checa, J. C., & García‐Ruiz, C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.099333 · Cited by 245
McKim, S. E., Gäbele, E., Isayama, F., Lambert, J. C., Tucker, L. M., Wheeler, M. D., Connor, H. D., Mason, R. P., Doll, M. A., Hein, D. W., et al. (2003) · Gastroenterology · doi:10.1053/j.gastro.2003.08.030 · Cited by 243
Hartley, D. P., Ruth, J. A., & Petersen, D. R. (1995) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1995.1028 · Cited by 243
An overview of the chemistry and biology of reactive aldehydes
Fritz, K. S., & Petersen, D. R. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.025 · Cited by 237 · cited 1×
“Recent results showed that highly-reactive lipid peroxides including 4-HNE and 4-ONE, despite their extremely short half-lives, can suppress the activities of many mitochondrial proteins likely through adduct formation with a few amino acids such as Cys, His, Arg, and Lys of target proteins [168].”
BackgroundMitochondrially targeted compounds and their impact on cellular bioenergetics
Reily, C., Mitchell, T., Chacko, B. K., Benavides, G. A., Murphy, M. P., & Darley-Usmar, V. M. (2013) · Redox Biology · doi:10.1016/j.redox.2012.11.009 · Cited by 227 · cited 1×
“In contrast to the SS-peptides or peptide-mimetics, a small molecule triphenyl phosphonium (TPPþ , a cell permeable lipophilic cation) has been developed to conjugate with various drugs and antioxidants to enhance the transport of target molecules to reduce oxidative stress and damage, as reviewed [222,223].”
BackgroundRadical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond
Daffu, G., Del Pozo, C., O'Shea, K., Ananthakrishnan, R., Ramasamy, R., & Schmidt, A. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141019891 · Cited by 222
Tanner, K. G., Trievel, R. C., Kuo, M., Howard, R. M., Berger, S. L., Allis, C. D., Marmorstein, R., & Denu, J. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.26.18157 · Cited by 221 · cited 1×
“These reports indicate that the characteristics of acetyltransferase(s) are poorly understood and need further studies, although the GCN5 family seems to be the prototype of (histone) acetyltransferases [161].”
BackgroundHinson, J. A., Pike, S. L., Pumford, N. R., & Mayeux, P. R. (1998) · Chemical Research in Toxicology · doi:10.1021/tx9800349 · Cited by 218 · cited 1×
“Hepatic necrosis highly correlated with the areas of nitrated proteins [91].”
BackgroundInvolvement of mammalian sirtuin 1 in the action of ethanol in the liver
You, M., Liang, X., Ajmo, J. M., & Ness, G. C. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00575.2007 · Cited by 216
The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction
Zhong, W., McClain, C. J., Cave, M., Kang, Y. J., & Zhou, Z. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00350.2009 · Cited by 214
JNK mediates hepatic ischemia reperfusion injury
Uehara, T., Bennett, B. L., Sakata, S. T., Satoh, Y., Bilter, G. K., Westwick, J. K., & Brenner, D. A. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.01.030 · Cited by 214
Mukhopadhyay, P., Horváth, B., Zsengellér, Z. K., Zielonka, J., Tanchian, G., Holovac, E., Kechrid, M., Patel, V., Stillman, I. E., Parikh, S. M., et al. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.001 · Cited by 212 · cited 1×
“The results with mitochondria-targeted ubiquinone (MitoQ) or mitochondria-targeted carboxy-proxyl (Mito-CP) so far have shown promising results in preventing mitochondrial abnormalities and nitroxidative tissue injury in various disease models including Friedreich Ataxia fibroblasts [224], diabetic nephropathy [225],…”
BackgroundPrevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ
Chacko, B. K., Reily, C., Srivastava, A., Johnson, M. S., Ye, Y., Ulasova, E., Agarwal, A., Zinn, K. R., Murphy, M. P., Kalyanaraman, B., et al. (2010) · Biochemical Journal · doi:10.1042/bj20100308 · Cited by 204
Inhibition by nitric oxide of the repair protein, O6-DNA-methyltransferase
Laval, F., & Wink, D. A. (1994) · Carcinogenesis · doi:10.1093/carcin/15.3.443 · Cited by 201
Han, D., Dara, L., Win, S., Than, T. A., Yuan, L., Abbasi, S. Q., Liu, Z., & Kaplowitz, N. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.01.009 · Cited by 198 · cited 4×
“dysfunction and acute liver injury [18–21,24].”
BackgroundInfluentialWin, S., Than, T. A., Han, D., Petrovic, L. M., & Kaplowitz, N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.276089 · Cited by 197 · cited 2×
“In addition, activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP [115,116,130,131].”
BackgroundHepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling
Schattenberg, J. M., Wang, Y., Singh, R., Rigoli, R. M., & Czaja, M. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410310200 · Cited by 194 · cited 1×
“In addition, activation of JNK was positively related to high fat diet-induced insulin resistance and metabolic syndrome [119,121–123].”
BackgroundCYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis
Abdelmegeed, M. A., Banerjee, A., Jang, S., Yoo, S.-H., Yun, J.-W., Gonzalez, F. J., Keshavarzian, A., & Song, B.-J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.09.009 · Cited by 191 · cited 1×
“However, we briefly describe the redox-mediated regulation of stress activated MAPKs and AMP-activated protein kinase (AMPK) in this review, based on their involvement in mitochondrial homeostasis, intermediary metabolism for steatosis and liver injury.”
BackgroundSelf-citationMitochondrial dysfunction and complications associated with diabetes
Blake, R., & Trounce, I. A. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.11.007 · Cited by 190 · cited 2×
“Parkinson's disease [4–12], although etiological causes of each disease are different.”
BackgroundGao, Z., Zhang, J., Kheterpal, I., Kennedy, N., Davis, R. J., & Ye, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228874 · Cited by 187 · cited 1×
“A recent study also showed that sustained JNK activation led to phosphorylation at Ser-46 of sirtuin 1, NADþ-dependent deacetylase in cytosol (described later), followed by ubiquitin-dependent degradation, contributing to fat accumulation in obese mice [124].”
BackgroundCritical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure
Henderson, N. C., Pollock, K. J., Frew, J. W., MacKinnon, A. C., Flavell, R. A., Davis, R. J., Sethi, T., & Simpson, K. J. (2006) · Gut · doi:10.1136/gut.2006.104372 · Cited by 183
Gong, P., & Cederbaum, A. I. (2005) · Hepatology · doi:10.1002/hep.21004 · Cited by 182 · cited 1×
“Activation of Nrf2 with its down-stream target proteins, including glutamate cysteine ligase, heme oxygenase-1, quinone reductase, and thioredoxin reductase, provides anti-oxidant defense against increased oxidative stress caused by alcohol exposure [62].”
BackgroundSIRT3 regulates mitochondrial protein acetylation and intermediary metabolism
Hirschey, M. D., Shimazu, T., Huang, J. Y., Schwer, B., & Verdin, E. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010850 · Cited by 180 · cited 1×
“As mentioned earlier, key mitochondrial proteins in regulating the fatty acid metabolism are acetylated and that the number of acetylated proteins can be significantly increased through suppression of the mitochondrial deacetylase sirtuin 3 and other sirtuin isoforms by alcohol [142–145,149,150–153], high fat [148], a…”
BackgroundPost-translational modifications of superoxide dismutase
Yamakura, F., & Kawasaki, H. (2009) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.10.010 · Cited by 179
Monda, M., Messina, G., Scognamiglio, I., Lombardi, A., Martin, G. A., Sperlongano, P., Porcelli, M., Caraglia, M., & Stiuso, P. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/131024 · Cited by 178
From fatty liver to fibrosis: A tale of “second hit”
Başaranoğlu, M. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i8.1158 · Cited by 177
Win, S., Than, T. A., Fernández-Checa, J. C., & Kaplowitz, N. (2014) · Cell Death and Disease · doi:10.1038/cddis.2013.522 · Cited by 174 · cited 1×
“One of the potential mechanisms of JNK translocation to mitochondria could be through its interaction with a scaffold protein Sab [116,134] or Bcl-XL [130] on the mitochondrial outer membrane before it gets transported into mitochondria.”
BackgroundDegradation of Damaged Proteins
Pickering, A. M., & Davies, K. J. A. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-397863-9.00006-7 · Cited by 173
Nlemelä, O., Parkkila, S., Ylä‐Herttuala, S., Villanueva, J. A., Ruebner, B. H., & Halsted, C. H. (1995) · Hepatology · doi:10.1002/hep.1840220428 · Cited by 172 · cited 2×
“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].”
BackgroundVenkatraman, A., Landar, A., Davis, A. J., Chamlee, L., Sanderson, T., Kim, H., Page, G., Pompilius, M., Ballinger, S., Darley-Usmar, V., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402245200 · Cited by 170 · cited 1×
“sistently observed by other groups [44,45].”
S-Glutathionylation signaling in cell biology: Progress and prospects
Pastore, A., & Piemonte, F. (2012) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2012.03.010 · Cited by 170 · cited 1×
“It is known that Cys-glutathionylation of mixed disulfide groups can create a functional cycle consisting of the forward reaction (glutathione S-transferase P) and the reverse reaction (glutaredoxin system) [67,73,74].”
BackgroundSantamaría, E., Avila, M. A., Latasa, M. U., Rubio, Á., Martín‐Duce, A., Lu, S. C.-L., Mato, J. M., & Corrales, F. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0536625100 · Cited by 170
SCHROETER, H., BOYD, C. S., AHMED, R., SPENCER, J. P. E., DUNCAN, R. F., RICE-EVANS, C., & CADENAS, E. (2003) · Biochemical Journal · doi:10.1042/bj20030201 · Cited by 169
Spruss, A., Kanuri, G., Stahl, C., Bischoff, S. C., & Bergheim, I. (2012) · Laboratory Investigation · doi:10.1038/labinvest.2012.75 · Cited by 168
Kohr, M. J., Sun, J., Aponte, A. M., Wang, G., Guček, M., Murphy, E., & Steenbergen, C. (2010) · Circulation Research · doi:10.1161/circresaha.110.232173 · Cited by 167
Spruss, A., & Bergheim, I. (2009) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2009.05.006 · Cited by 162
Wine Polyphenols: Potential Agents in Neuroprotection
Basli, A., Soulet, S., Chaher, N., Mérillon, J., Chibane, M., Monti, J., & Richard, T. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/805762 · Cited by 162 · cited 2×
“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].”
BackgroundGenetic insights into OXPHOS defect and its role in cancer
Chandra, D., & Singh, K. K. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.10.023 · Cited by 155 · cited 1×
“Interestingly, mitochondrial DNA encodes 13 polypeptides all of which are members of the 4 mitochondrial ETC proteins, namely Complexes I, III, IV, and V [82,83].”
Background(De)constructing Mitochondria: What For?
Dimmer, K. S., & Scorrano, L. (2006) · Physiology · doi:10.1152/physiol.00010.2006 · Cited by 151
Nonenzymatic acetylation of histones with acetyl-CoA
Paik, W. K., Pearson, D., Lee, H. W., & Kim, S. (1970) · Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis · doi:10.1016/0005-2787(70)90058-4 · Cited by 151 · cited 1×
“In addition, other studies indicated that protein acetylation can take place nonenzymatically in the presence of low levels of acetyl-CoA [159] or acetyl-phosphate and acetyl-adenylate [160].”
BackgroundNIEMELA, O. (1995) · Hepatology · doi:10.1016/0270-9139(95)90630-4 · Cited by 149
Antioxidants as therapies: can we improve on nature?
Murphy, M. P. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.010 · Cited by 148 · cited 1×
“CYP2E1, one of the main enzymes involved in APAP metabolism, seems to play a critical role in APAP-induced protein nitration and liver injury [93].”
BackgroundCysteine Modification by Lipid Peroxidation Products Inhibits Protein Disulfide Isomerase
Carbone, D. L., Doorn, J. A., Kiebler, Z., & Petersen, D. R. (2005) · Chemical Research in Toxicology · doi:10.1021/tx050078z · Cited by 148 · cited 1×
“In addition, many other proteins such as protein disulfide isomerase [174] and Grp78 [175] in the ER, gamma-glutamyl-cysteine synthase (GCS) [176], ERK [177], PTEN [178], or AMPK [179] in cytosol could also be inactivated through interaction with 4-HNE, likely leading to ER stress, GSH depletion and alteration of the…”
BackgroundGambino, R., Musso, G., & Cassader, M. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3058 · Cited by 147 · cited 2×
“Parkinson's disease [4–12], although etiological causes of each disease are different.”
BackgroundLipid peroxidation contributes to immune reactions associated with alcoholic liver disease
Mottaran, E., Stewart, S. F., Rolla, R., Vay, D., Cipriani, V., Moretti, M., Vidali, M., Sartori, M., Rigamonti, C., Day, C. P., et al. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00757-2 · Cited by 145 · cited 1×
“In fact, the average levels of MDA- and HNE-protein adducts in 50 alcoholic cirrhosis patients were significantly higher than those in a similar number of patients with nonalcoholic cirrhosis or healthy individuals [180].”
ResultFrench, S. W., Wong, K., Jui, L., Albano, E., Hagbjörk, A.-L., & Ingelman‐Sundberg, M. (1993) · Experimental and Molecular Pathology · doi:10.1006/exmp.1993.1006 · Cited by 143 · cited 1×
“Without proper counter-balance by various cellular anti-oxidants, the persistent imbalance in cellular redox states result in decreased levels of mitochondrial antioxidants including mitochondrial glutathione (mtGSH), which serves as a critical determinant between toxic damage and cellular…”
BackgroundMitochondrial Morphology in Metabolic Diseases
Galloway, C. A., & Yoon, Y. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4779 · Cited by 143 · cited 1×
“Recent reports showed that mitochondria also undergo constant morphological changes with fusion and fission, following the exposure to toxic agents and/or under pathological conditions [2,3].”
BackgroundInfluentialVetreno, R. P., Qin, L., & Crews, F. T. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.002 · Cited by 141 · cited 1×
“These results are in agreement with the increased expression of RAGE in the brains of alcohol-exposed rats and humans [200].”
ResultResveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation
Yang, S. J., & Lim, Y. (2014) · Metabolism · doi:10.1016/j.metabol.2014.02.003 · Cited by 141 · cited 1×
“small molecule polyphenols including resveratrol [156] and green”
BackgroundRole of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease
Sid, B., Verrax, J., & Calderón, P. B. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.05.007 · Cited by 141 · cited 2×
“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].”
BackgroundCalcerrada, P., Peluffo, G., & Radí, R. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211798357719 · Cited by 141
Inhibition of Human Mitochondrial Aldehyde Dehydrogenase by 4-Hydroxynon-2-enal and 4-Oxonon-2-enal
Doorn, J. A., Hurley, T. D., & Petersen, D. R. (2006) · Chemical Research in Toxicology · doi:10.1021/tx0501839 · Cited by 140 · cited 1×
“They showed that the active site Cys301 of ALDH2 [173] and Cys280 in the critical Zn binding site of sirtuin 3 [151] were covalently modified with 4-HNE, leading to their inactivation.”
BackgroundRole of 4-Hydroxynonenal in Modification of Cytochrome c Oxidase in Ischemia/Reperfused Rat Heart
Chen, J., Henderson, G. I., & Freeman, G. L. (2001) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2001.1454 · Cited by 138 · cited 1×
“In case of high-fat fed rodents, the total number of the reports on HNE-protein adducts in the livers of NAFLD seems relatively small compared to those in AFLD, although the identities of HNE-protein adducts were reported in extra-hepatic tissues such as heart [183,184].”
ResultInactivation of NADP+-dependent Isocitrate Dehydrogenase by Peroxynitrite
Lee, J. H., Yang, E. S., & Park, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302332200 · Cited by 137
Zou, X., Yan, C., Shi, Y., Cao, K. J., Xu, J., Wang, X., Chen, C., Luo, C. Y., Li, Y., Gao, J., et al. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5538 · Cited by 135
Effect of chronic alcohol consumption on Hepatic SIRT1 and PGC-1α in rats
Lieber, C. S., Leo, M. A., Wang, X., & DeCarli, L. M. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.03.005 · Cited by 135 · cited 4×
“gamma coactivator-1 (PGC-1), forkhead box protein O1 (FoxO1), NFκB and p53 [142–144,149].”
BackgroundInfluentialKirpich, I. A., Feng, W., Wang, Y., Liu, Y., Barker, D. F., Barve, S. S., & McClain, C. J. (2012) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2011.01673.x · Cited by 135
Mukhopadhyay, P., Horváth, B., Zsengellér, Z. K., Bátkai, S., Cao, Z., Kechrid, M., Holovac, E., Erdélyi, K., Tanchian, G., Liaudet, L., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.05.036 · Cited by 132 · cited 2×
“In addition, the protective effects of MitoQ and Mito-CP were clearly demonstrated in a mouse model of hepatic I/ R injury [228].”
BackgroundZhang, Y., Mi, S., Hu, N., Doser, T. A., Sun, A., Ge, J., & Ren, J. T. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.03.018 · Cited by 132
Bae, M., & Song, B. J. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.2.401 · Cited by 129 · cited 1×
“In fact, acute exposure to many hepatotoxic agents including alcohol [110,111], APAP [112–116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”
BackgroundSelf-citation4-hydroxynonenal inhibits SIRT3 via thiol-specific modification
Fritz, K. S., Galligan, J. J., Smathers, R. L., Roede, J. R., Shearn, C. T., Reigan, P., & Petersen, D. R. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100355a · Cited by 127 · cited 1×
“They showed that the active site Cys301 of ALDH2 [173] and Cys280 in the critical Zn binding site of sirtuin 3 [151] were covalently modified with 4-HNE, leading to their inactivation.”
BackgroundStill, A. J., Floyd, B. J., Hebert, A. S., Bingman, C. A., Carson, J. J., Gunderson, D. R., Dolan, B. K., Grimsrud, P. A., Dittenhafer-Reed, K. E., Stapleton, D. S., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.483396 · Cited by 123
Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis
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. (2011) · Hepatology · doi:10.1002/hep.24377 · Cited by 122
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Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent
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BackgroundInactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats
Moon, K.-H., Hood, B. L., Kim, B.-J., Hardwick, J. P., Conrads, T. P., Veenstra, T. D., & Song, B. J. (2006) · Hepatology · doi:10.1002/hep.21372 · Cited by 120 · cited 7×
“exposed rats was fully restored by DDT treatment [34].”
BackgroundInfluentialSelf-citationThe role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice
Venkatraman, A., Shiva, S., Wigley, A., Ulasova, E., Chhieng, D., Bailey, S. M., & Darley-Usmar, V. M. (2004) · Hepatology · doi:10.1002/hep.20326 · Cited by 117
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Nutrition and Healthy Ageing: Calorie Restriction or Polyphenol-Rich “MediterrAsian” Diet?
Pallauf, K., Giller, K., Huebbe, P., & Rimbach, G. H. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/707421 · Cited by 116 · cited 2×
“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 [27,75–77].”
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“This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). nced glycation end product; ACR, acrolein; AFLD, alcoholic fatty liver disease;…”
BackgroundInfluentialSelf-citationPleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease
Davinelli, S., Sapere, N., Zella, D., Bracale, R., Intrieri, M., & Scapagnini, G. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/386527 · Cited by 114
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“Furthermore, some Cys residues can be modified through adduct formation with carbonyl compounds, including lipid peroxide 4-hydroxy-2-nonenal (4-HNE) and reactive metabolites of APAP.”
BackgroundTributyrin Supplementation Protects Mice from Acute Ethanol-Induced Gut Injury
Cresci, G., Bush, K., & Nagy, L. E. (2014) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12428 · Cited by 113
S-nitrosylation: A radical way to protect the heart
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“(Cys-SO2) and Cys-sulfonic acid (Cys-SO3) followed by proteolytic degradation [67,68], as in the case of I/R injury [69–72].”
MethodS-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver
Bailey, S. M., Robinson, G., Pinner, A. L., Chamlee, L., Ulasova, E., Pompilius, M., Page, G. P., Chhieng, D., Jhala, N. C., Landar, A. L., et al. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00044.2006 · Cited by 110
Niemelä, O., Parkkila, S., Pasanen, M., Limuro, Y., Bradford, B., & Thurman, R. G. (1998) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.1998.tb05925.x · Cited by 107 · cited 1×
“Without proper counter-balance by various cellular anti-oxidants, the persistent imbalance in cellular redox states result in decreased levels of mitochondrial antioxidants including mitochondrial glutathione (mtGSH), which serves as a critical determinant between toxic damage and cellular…”
BackgroundDunagan, M., Chaudhry, K., Samak, G., & Rao, R. K. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00526.2011 · Cited by 103
Moon, K., Hood, B. L., Mukhopadhyay, P., Rajesh, M., Abdelmegeed, M. A., Kwon, Y., Conrads, T. P., Veenstra, T. D., Song, B., & Pacher, P. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.048 · Cited by 103 · cited 4×
“and inactivation of ALDH2 were also observed after exposure to MDMA [39] or I/R injury [38], resulting in the accumulation of”
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Valdecantos, M. P., Pérez‐Matute, P., González‐Muniesa, P., Prieto-Hontoria, P. L., Moreno-Aliaga, M. J., & Martínez, J. A. (2012) · Obesity · doi:10.1038/oby.2012.32 · Cited by 94
Bae, S. H., Sung, S. H., Cho, E. J., Lee, S. K., Lee, H. E., Woo, H. A., Yu, D.-Y., Kil, I. S., & Rhee, S. G. (2011) · Hepatology · doi:10.1002/hep.24104 · Cited by 93 · cited 18×
“In addition, we highlight potential roles of CYP2E1 in promoting various PTMs. Post-translational modifications of mitochondrial proteins”
BackgroundInfluentialMitochondrial off targets of drug therapy
Wallace, K. B. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.04.001 · Cited by 90 · cited 1×
“Interestingly, mitochondrial DNA encodes 13 polypeptides all of which are members of the 4 mitochondrial ETC proteins, namely Complexes I, III, IV, and V [82,83].”
BackgroundSaberi, B., Ybanez, M. D., Johnson, H. S., Gaarde, W. A., Han, D., & Kaplowitz, N. (2014) · Hepatology · doi:10.1002/hep.26625 · Cited by 88
Human Microglial Cells Synthesize Albumin in BrainPreprint
Ahn, S., Byun, K., Cho, K., Kim, J. Y., Yoo, J. S., Kim, D., Paek, S. H., Kim, S. U., Simpson, R. J., & Lee, B. (2008) · Nature Precedings · doi:10.1371/journal.pone.0002829 · Cited by 87 · cited 1×
“Consistently, the elevated amounts of AGE-albumin, which was confirmed by mass-spectral analysis [201], were found in the brains of Alzheimer’s disease patients than those of the healthy”
BackgroundSelf-citationSignaling Pathways Mediating Alcohol Effects
Dorit Ron, A., & Messing, R. O. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2011_161 · Cited by 85 · cited 1×
“In fact, crosstalk between different classes of protein kinases becomes complicated, contributing to different outcomes, depending on their inducibility, tissue distribution, subcellular localization or translocation to another compartment, cellular environment, treatment agent, and activity status of phosphoprotein p…”
BackgroundCytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver
Yang, L., Wu, D., Wang, X., & Cederbaum, A. I. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.029 · Cited by 85
Abdelmegeed, M. A., Jang, S., Banerjee, A., Hardwick, J. P., & Song, B.-J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.02.018 · Cited by 85 · cited 8×
“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.”
BackgroundMethodInfluentialLi, C., Nanji, A. A., Siakotos, A. N., & Lin, R. C. (1997) · Hepatology · doi:10.1002/hep.510260317 · Cited by 85 · cited 3×
“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].”
BackgroundOxidative modification of hepatic mitochondria protein thiols: effect of chronic alcohol consumption
Venkatraman, A., Landar, A., Davis, A. J., Ulasova, E., Page, G., Murphy, M. P., Darley-Usmar, V., & Bailey, S. M. (2004) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00399.2003 · Cited by 85 · cited 1×
“sistently observed by other groups [44,45].”
Kharbanda, K. K., Todero, S. L., King, A. L., Osna, N. A., McVicker, B. L., Tuma, D. J., Wisecarver, J. L., & Bailey, S. M. (2011) · International Journal of Hepatology · doi:10.1155/2012/962183 · Cited by 83
González-Guerrico, A. M., & Kazanietz, M. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506767200 · Cited by 83 · cited 1×
“For instance, concurrent activation of PKC-delta isoform along with stress activated protein kinases generally enhances cell death [106–108], although some exceptions exist.”
BackgroundMontfort, C. V., Matias, N., Fernandez, A., Fucho, R., de la Rosa, L. C., Martinez-Chantar, M. L., Mato, J. M., Machida, K., Tsukamoto, H., Murphy, M. P., et al. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.05.024 · Cited by 83
Kim, B., Hood, B. L., Aragon, R. A., Hardwick, J. P., Conrads, T. P., Veenstra, T. D., & Song, B. J. (2006) · PROTEOMICS · doi:10.1002/pmic.200500447 · Cited by 83
Self-citationAbdelmegeed, M. A., Moon, K.-H., Chen, C., Gonzalez, F. J., & Song, B.-J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.07.016 · Cited by 81 · cited 1×
“CYP2E1, one of the main enzymes involved in APAP metabolism, seems to play a critical role in APAP-induced protein nitration and liver injury [93].”
BackgroundSelf-citationRole for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability
Forsyth, C. B., Voigt, R. M., Shaikh, M. W., Tang, Y., Cederbaum, A. I., Turek, F. W., & Keshavarzian, A. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00354.2012 · Cited by 80
Role of the Inducible Nitric Oxide Synthase in the Onset of Fructose-Induced Steatosis in Mice
Spruss, A., Kanuri, G., Uebel, K., Bischoff, S. C., & Bergheim, I. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3263 · Cited by 79
Protein nitrotryptophan: Formation, significance and identification
Nuriel, T., Hansler, A., & Gross, S. S. (2011) · Journal of Proteomics · doi:10.1016/j.jprot.2011.05.032 · Cited by 78
Inactivation of NADP+-dependent isocitrate dehydrogenase by nitric oxide
Yang, E. S., Richter, C., Chun, J., Huh, T., Kang, S., & Park, J. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00981-4 · Cited by 78
Suh, S., Hood, B. L., Kim, B., Conrads, T. P., Veenstra, T. D., & Song, B. J. (2004) · PROTEOMICS · doi:10.1002/pmic.200400971 · Cited by 76 · cited 16×
“In addition, we highlight potential roles of CYP2E1 in promoting various PTMs. Post-translational modifications of mitochondrial proteins”
BackgroundInfluentialSelf-citationInduction of Neuronal Death by Microglial AGE-Albumin: Implications for Alzheimer’s Disease
Byun, K., Bayarsaikhan, E., Kim, D., Kim, C. Y., Mook-Jung, I., Paek, S. H., Kim, S. U., Yamamoto, T., Won, M.-H., Song, B.-J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037917 · Cited by 75
Self-citationProtein Carbonylation in a Murine Model for Early Alcoholic Liver Disease
Galligan, J. J., Smathers, R. L., Fritz, K. S., Epperson, L. E., Hunter, L. E., & Petersen, D. R. (2012) · Chemical Research in Toxicology · doi:10.1021/tx300002q · Cited by 74
Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications
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“In the case of oxidative inactivation of mitochondrial ALDH2 through active site Cys modification [42], immunoblot analysis of the immunoaffinity purified ALDH2 proteins by using the specific”
BackgroundMethodResultInfluentialKirpich, I., Feng, W., Wang, Y., Liu, Y., Beier, J. I., Arteel, G. E., Falkner, K. C., Barve, S. S., & McClain, C. J. (2013) · Alcohol · doi:10.1016/j.alcohol.2013.01.005 · Cited by 73
Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide‐mediated S‐nitrosylation
Moon, K., Kim, B., & Song, B. J. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.09.082 · Cited by 73 · cited 1×
“and 3-morpholino-sydnonimine, respectively [43].”
Self-citationThe effect of ethanol-induced CYP2E1 on proteasome activity: the role of 4-hydroxynonenal
Bardag‐Gorce, F., Li, J., French, B. A., & French, S. W. (2005) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2004.10.005 · Cited by 72 · cited 1×
“The ethanol-induced CYP2E1 was partly responsible for the production of 37 kD-acetaldehyde protein adducts [181] while 4-HNE protein adduct could be produced in CYP2E1-independent manner, although CYP2E1 seems to at least play a permissive role [182].”
BackgroundMechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage
Song, B., Moon, K., Upreti, V. V., Eddington, N. D., & Lee, I. J. (2010) · Current Pharmaceutical Biotechnology · doi:10.2174/138920110791591436 · Cited by 71
Self-citationAlcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function
Lieber, C. S., Leo, M. A., Wang, X., & DeCarli, L. M. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.06.006 · Cited by 71
Mitochondria: the gateway for tamoxifen-induced liver injury
Ribeiro, M. P. C., Santos, A. E., & Custódio, J. B. A. (2014) · Toxicology · doi:10.1016/j.tox.2014.05.009 · Cited by 70 · cited 1×
“In addition, acute or sub-chronic exposure to various hepatotoxic compounds, including clinically-used drugs, such as acetaminophen (APAP) [18–20], a major ingredient of Tylenol, an anti-breast cancer agent tamoxifen [21], an anti-retroviral drug zidovudine (AZT) [22] and antidepressants [23], can cause mitochondrial…”
BackgroundLee, Y. J., & Shukla, S. D. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.12.006 · Cited by 70 · cited 1×
“In fact, acute exposure to many hepatotoxic agents including alcohol [110,111], APAP [112–116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”
BackgroundWang, Z., Dou, X., Li, S., Zhang, X., Sun, X., Zhou, Z., & Song, Z. (2013) · Hepatology · doi:10.1002/hep.26912 · Cited by 69 · cited 1×
“under increased oxidative stress in AFLD and NAFLD [62–65].”
BackgroundShearn, C. T., Smathers, R. L., Backos, D. S., Reigan, P., Orlicky, D. J., & Petersen, D. R. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.011 · Cited by 69 · cited 3×
“In addition, many other proteins such as protein disulfide isomerase [174] and Grp78 [175] in the ER, gamma-glutamyl-cysteine synthase (GCS) [176], ERK [177], PTEN [178], or AMPK [179] in cytosol could also be inactivated through interaction with 4-HNE, likely leading to ER stress, GSH depletion and alteration of the…”
BackgroundChronic Ethanol Consumption Induces Global Hepatic Protein Hyperacetylation
Shepard, B. D., Tuma, D. J., & Tuma, P. L. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.01091.x · Cited by 68 · cited 3×
“alcohol-exposed [142–145] or high-fat exposed rodents [146–148].”
BackgroundRedox Signaling and the Innate Immune System in Alcoholic Liver Disease
Cohen, J. I., Chen, X., & Nagy, L. E. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3746 · Cited by 68 · cited 1×
“For instance, NF-κB, a critical transcription factor in inflammation and innate immune regulation, can be activated by alcohol [56] and other toxic agents such as lipopolysaccharide (LPS) [57].”
BackgroundSignaling Pathways Mediating Alcohol Effects
Ron, D., & Messing, R. O. (2011) · Current topics in behavioral neurosciences · doi:10.1007/978-3-642-28720-6_161 · Cited by 68
Song, B.-J., Abdelmegeed, M. A., Henderson, L. E., Yoo, S.-H., Wan, J., Purohit, V., Hardwick, J. P., & Moon, K.-H. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/781050 · Cited by 67 · cited 6×
“As recently reviewed [26,27], Cys residue(s) can be oxidatively modified in many forms [sulfenic acid, disulfide, sulfinic/sulfonic acids, NOor peroxynitrite-dependent S-nitrosylation, NO-independent ADPribosylation, mixed disulfide formation between Cys residues and glutathione (glutathionylation), cysteine (cystathi…”
BackgroundMethodInfluentialSelf-citationNitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes
Zelickson, B. R., Benavides, G. A., Johnson, M. S., Chacko, B. K., Venkatraman, A., Landar, A. L., Betancourt, A. M., Bailey, S. M., & Darley-Usmar, V. M. (2011) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2011.09.011 · Cited by 66 · cited 1×
“Chronic or acute alcohol exposure and other hepatotoxic agents can also activate HIF-1α in mice and rats [57,58–61].”
BackgroundMali, V., Ning, R., Chen, J., Yang, X.-P., Xu, J., & Palaniyandi, S. S. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370213520109 · Cited by 65 · cited 2×
“In fact, ALDH2 activity in the heart was significantly inhibited in high fat-exposed diabetic mice [186].”
BackgroundVergeade, A., Mulder, P. G. H., Vendeville, C., Estour, F., Fortin, D., Ventura‐Clapier, R., Thuillez, C., & Monteil, C. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.05.024 · Cited by 64 · cited 1×
“The results with mitochondria-targeted ubiquinone (MitoQ) or mitochondria-targeted carboxy-proxyl (Mito-CP) so far have shown promising results in preventing mitochondrial abnormalities and nitroxidative tissue injury in various disease models including Friedreich Ataxia fibroblasts [224], diabetic nephropathy [225],…”
BackgroundSampey, B. P., Stewart, B. J., & Petersen, D. R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610602200 · Cited by 64 · cited 1×
“The number of oxidatively-modified mitochondrial proteins we characterized may represent a small fraction of the estimated number of 1100– 1400 total mitochondrial proteins [40,41].”
BackgroundRyer, E. J., Sakakibara, K., Wang, C., Sarkar, D., Fisher, P. B., Faries, P. L., Kent, K. C., & Liu, B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507187200 · Cited by 63 · cited 1×
“For instance, concurrent activation of PKC-delta isoform along with stress activated protein kinases generally enhances cell death [106–108], although some exceptions exist.”
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Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases
Mansouri, A., Gattolliat, C., & Asselah, T. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.06.083 · Cited by 839
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“, 2010), alcoholic fatty liver disease (AFLD) (Song et al., 2014), diabetes (Rolo & Palmeira, 2006), and chondrocyte degeneration (Blanco et al.”
Self-citationRepairing mitochondrial dysfunction in disease
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“Increased hepatic CYP2E1 is known to directly cause fatty liver disease by elevating oxidative/nitrative stress and various forms of posttranslational modification of cellular proteins, contributing to endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis of hepatocytes.(32) Furthermore, intestinal CY…”
BackgroundSelf-citation
Metadata
- 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)
- 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
- gold
- doi.org
- 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
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