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

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].”

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

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].”

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

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.”

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

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].”

What the sources say

• Not checked yetcites [193] Hayashi, 2013, Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease, PloS One source

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.”

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].”

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

In the paper

“Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated.”

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”

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

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.”

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.”

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].”

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

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].”

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

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].”

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

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].”

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

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.”

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

In the paper

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

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].”

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

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].”

What the sources say

• Not checked yetcites [42] Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics source

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].”

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

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].”

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

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.”

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

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].”

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

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].”

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

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].”

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

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.”

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.”

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.”

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