Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases

Mitochondria regulate hepatic lipid metabolism and oxidative stress. Ultrastructural mitochondrial lesions, altered mitochondrial dynamics, decreased activity of respiratory chain complexes, and impaired ability to synthesize adenosine triphosphate are observed in liver tissues from patients with alcohol-associated and non-associated liver diseases. Increased lipogenesis with decreased fatty acid β-oxidation leads to the accumulation of triglycerides in hepatocytes, which, combined with increased levels of reactive oxygen species, contributes to insulin resistance in patients with steatohepatitis. Moreover, mitochondrial reactive oxygen species mediate metabolic pathway signaling; alterations in these pathways affect development and progression of chronic liver diseases. Mitochondrial stress and lesions promote cell death, liver fibrogenesis, inflammation, and the innate immune responses to viral infections. We review the involvement of mitochondrial processes in development of chronic liver diseases, such as nonalcoholic fatty, alcohol-associated, and drug-associated liver diseases, as well as hepatitis B and C, and discuss how they might be targeted therapeutically. Mitochondria regulate hepatic lipid metabolism and oxidative stress. Ultrastructural mitochondrial lesions, altered mitochondrial dynamics, decreased activity of respiratory chain complexes, and impaired ability to synthesize adenosine triphosphate are observed in liver tissues from patients with alcohol-associated and non-associated liver diseases. Increased lipogenesis with decreased fatty acid β-oxidation leads to the accumulation of triglycerides in hepatocytes, which, combined with increased levels of reactive oxygen species, contributes to insulin resistance in patients with steatohepatitis. Moreover, mitochondrial reactive oxygen species mediate metabolic pathway signaling; alterations in these pathways affect development and progression of chronic liver diseases. Mitochondrial stress and lesions promote cell death, liver fibrogenesis, inflammation, and the innate immune responses to viral infections. We review the involvement of mitochondrial processes in development of chronic liver diseases, such as nonalcoholic fatty, alcohol-associated, and drug-associated liver diseases, as well as hepatitis B and C, and discuss how they might be targeted therapeutically. Alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD) can progress from benign steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma. Obesity, alcohol, drug use, and chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) are all associated, to different degrees, with increased prevalence of steatosis, characterized by the accumulation of fat droplets within the hepatocytes.1Pessayre D. Berson A. Fromenty B. et al.Mitochondria in steatohepatitis.Semin Liver Dis. 2001; 21: 57-69Crossref PubMed Google Scholar, 2Vacca M. Allison M. Griffin J.L. et al.Fatty acid and glucose sensors in hepatic lipid metabolism: implications in NAFLD.Semin Liver Dis. 2015; 35: 250-261Crossref PubMed Scopus (11) Google Scholar, 3Pessayre D. Mansouri A. Fromenty B. Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G193-F199Crossref PubMed Google Scholar, 4Koliaki C. Szendroedi J. 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Berson A. et al.Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients.J Hepatol. 1997; 27: 96-102Abstract Full Text PDF PubMed Scopus (109) Google Scholar Steatosis remains benign in most patients, but in some cases leads to hepatocyte necrosis, infiltration of inflammatory cells, and progressive development of fibrosis into cirrhosis.1Pessayre D. Berson A. Fromenty B. et al.Mitochondria in steatohepatitis.Semin Liver Dis. 2001; 21: 57-69Crossref PubMed Google Scholar, 2Vacca M. Allison M. Griffin J.L. et al.Fatty acid and glucose sensors in hepatic lipid metabolism: implications in NAFLD.Semin Liver Dis. 2015; 35: 250-261Crossref PubMed Scopus (11) Google Scholar The association of steatosis with these other liver lesions is called steatohepatitis.3Pessayre D. Mansouri A. Fromenty B. Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G193-F199Crossref PubMed Google Scholar, 4Koliaki C. Szendroedi J. Kaul K. et al.Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.Cell Metab. 2015; 21: 739-746Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 5Tell G. Vascotto C. Tiribelli C. Alterations in the redox state and liver damage: hints from the EASL Basic School of Hepatology.J Hepatol. 2013; 58: 365-374Abstract Full Text Full Text PDF PubMed Google Scholar Steatohepatitis associates with central obesity, steatosis, diabetes, hyperlipidemia, and insulin resistance (IR).2Vacca M. Allison M. Griffin J.L. et al.Fatty acid and glucose sensors in hepatic lipid metabolism: implications in NAFLD.Semin Liver Dis. 2015; 35: 250-261Crossref PubMed Scopus (11) Google Scholar, 4Koliaki C. Szendroedi J. Kaul K. et al.Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.Cell Metab. 2015; 21: 739-746Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar In addition to obesity-associated steatohepatitis, there are more-severe forms of fatty liver, associated with alcohol excess,6Altamirano J. Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy.Nat Rev Gastroenterol Hepatol. 2011; 8: 491-501Crossref PubMed Scopus (137) Google Scholar, 7Mansouri A. Fromenty B. Berson A. et al.Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients.J Hepatol. 1997; 27: 96-102Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 8Lucey M.R. Mathurin P. Morgan T.R. Alcoholic hepatitis.N Engl J Med. 2009; 360: 2758-2769Crossref PubMed Scopus (447) Google Scholar some drugs,9Pessayre D. Fromenty B. Berson A. et al.Central role of mitochondria in drug-induced liver injury.Drug Metab Rev. 2012; 44: 34-87Crossref PubMed Scopus (116) Google Scholar, 10Larosche I. Lettéron P. Fromenty B. et al.Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver.J Pharmacol Exp Ther. 2007; 321: 526-535Crossref PubMed Scopus (0) Google Scholar, 11Begriche K. Massart J. Robin M.-A. et al.Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.J Hepatol. 2011; 54: 773-794Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar or chronic HBV or HCV infection.3Pessayre D. Mansouri A. Fromenty B. Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G193-F199Crossref PubMed Google Scholar, 4Koliaki C. Szendroedi J. 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Beard M.R. et al.Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology. 2002; 122: 366-375Abstract Full Text Full Text PDF PubMed Google Scholar Mitochondrial dysfunction and oxidative stress have been detected in liver tissues from patients with steatosis and IR, diabetes, non-alcoholic steatohepatitis (NASH), or various stages of alcoholic steatohepatitis (ASH).1Pessayre D. Berson A. Fromenty B. et al.Mitochondria in steatohepatitis.Semin Liver Dis. 2001; 21: 57-69Crossref PubMed Google Scholar, 2Vacca M. Allison M. Griffin J.L. et al.Fatty acid and glucose sensors in hepatic lipid metabolism: implications in NAFLD.Semin Liver Dis. 2015; 35: 250-261Crossref PubMed Scopus (11) Google Scholar, 3Pessayre D. Mansouri A. Fromenty B. Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G193-F199Crossref PubMed Google Scholar, 4Koliaki C. Szendroedi J. Kaul K. et al.Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.Cell Metab. 2015; 21: 739-746Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 5Tell G. Vascotto C. Tiribelli C. Alterations in the redox state and liver damage: hints from the EASL Basic School of Hepatology.J Hepatol. 2013; 58: 365-374Abstract Full Text Full Text PDF PubMed Google Scholar, 6Altamirano J. Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy.Nat Rev Gastroenterol Hepatol. 2011; 8: 491-501Crossref PubMed Scopus (137) Google Scholar, 7Mansouri A. Fromenty B. Berson A. et al.Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients.J Hepatol. 1997; 27: 96-102Abstract Full Text PDF PubMed Scopus (109) Google Scholar, 8Lucey M.R. Mathurin P. Morgan T.R. Alcoholic hepatitis.N Engl J Med. 2009; 360: 2758-2769Crossref PubMed Scopus (447) Google Scholar, 9Pessayre D. Fromenty B. Berson A. et al.Central role of mitochondria in drug-induced liver injury.Drug Metab Rev. 2012; 44: 34-87Crossref PubMed Scopus (116) Google Scholar, 10Larosche I. Lettéron P. Fromenty B. et al.Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver.J Pharmacol Exp Ther. 2007; 321: 526-535Crossref PubMed Scopus (0) Google Scholar, 11Begriche K. Massart J. 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Mitochondrial fusion, fission, biogenesis, and mitophagy determine mitochondrial morphology, quality, and abundance, and are tightly controlled in response to metabolic cues and stressors to ensure adaptation of mitochondrial function to cellular energetic and metabolic demands. Fusion of the MOM is mediated by mitofusins 1 and 2, whereas the fusion of MIM requires optic atrophy protein 1.17Cipolat S. Martins de Brito O. Dal Zilio B. et al.OPA1 requires mitofusin 1 to promote mitochondrial fusion.Proc Natl Acad Sci U S A. 2004; 9;101: 15927-15932Crossref Scopus (582) Google Scholar Mitochondrial fission requires dynamin-related protein 1, which is recruited by the mitochondrial fission 1 protein.18Hall A.R. Burke N. Dongworth R.K. et al.Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease.Br J Pharmacol. 2014; 171: 1890-1906Crossref PubMed Scopus (63) Google Scholar Mitochondrial biogenesis maintains mitochondrial mass to restore energy homeostasis during energy deprivation or following mitochondrial insults. Mitochondrial biogenesis is regulated by peroxisome proliferator–activated receptor gamma coactivator 1α (PPARGC1A or PGC-1α) and nuclear respiratory factor 1 (NRF1), which control expression of mtDNA and nuclear DNA genes encoding subunits of the MRC complexes and mtDNA replication and transcription, respectively.19St-Pierre J. Drori S. Uldry M. et al.Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.Cell. 2006; 127: 397-408Abstract Full Text Full Text PDF PubMed Scopus (1238) Google Scholar, 20Cantó C. Auwerx J. 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A mechanistic review of mitophagy and its role in protection against alcoholic liver disease.Biomolecules. 2015; 5: 2619-2642Crossref PubMed Google Scholar The mitochondrial unfolded protein response (mtUPR) maintains mitochondrial homeostasis, controls the stochiometric balance between proteins encoded by the nuclear and mitochondrial genomes, ensures mitochondrial quality and proteostasis, and senses mitochondrial protein misfolding.24Mottis A. Jovaisaite V. Auwerx J. The mitochondrial unfolded protein response in mammalian physiology.Mamm Genome. 2014; 25: 424-433Crossref PubMed Scopus (0) Google Scholar, 25Fiorese C.J. Schulz A.M. Lin Y.-F. et al.The Transcription factor ATF5 mediates a mammalian mitochondrial UPR.Curr Biol. 2016; 26: 2037-2043Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Mitochondria are required for fat metabolism and energy production, the urea cycle, and metabolism of amino acids and iron,1Pessayre D. Berson A. 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McGill M.R. et al.Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity.Food Chem Toxicol. 2017; 108: 339-350Crossref PubMed Scopus (3) Google Scholar, 23Williams J.A. Ding W.-X. A mechanistic review of mitophagy and its role in protection against alcoholic liver disease.Biomolecules. 2015; 5: 2619-2642Crossref PubMed Google Scholar, 26Herzig S. Shaw R.J. AMPK: guardian of metabolism and mitochondrial homeostasis.Nat Rev Mol Cell Biol. 2018; 19: 121-135Crossref PubMed Scopus (29) Google Scholar, 28Meakin P.J. Chowdhry S. Sharma R.S. et al.Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance.Mol Cell Biol. 2014; 34: 3305-3320Crossref PubMed Google Scholar, 29Win S. Than T.A. 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Manganese superoxide dismutase allows the spontaneous dismutation of the O2.– into oxygen and H2O2, which is then detoxified into water by mitochondrial glutathione (GSH) peroxidase and peroxiredoxins.39Kotiadis V.N. Duchen M.R. Osellame L.D. Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health.Biochim Biophys Acta. 2014; 1840: 1254-1265Crossref PubMed Scopus (60) Google Scholar, 40Cox A.G. Winterbourn C.C. Hampton M.B. Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling.Biochem J. 2009; 425: 313-325Crossref PubMed Scopus (235) Google Scholar Alternatively, H2O2 reacts with iron to form the highly reactive hydroxyl radical39Kotiadis V.N. Duchen M.R. Osellame L.D. 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Beside their damaging effects, mitochondrial ROS are also signal-transducing molecules under physiological and pathological conditions, depending on the intensity and duration of oxidative stress.27Finkel T. Signal transduction by mitochondrial oxidants.J Biol Chem. 2012; 287: 4434-4440Crossref PubMed Scopus (164) Google Scholar, 29Win S. Than T.A. Zhang J. et al.New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases.Hepatology. 2018; 67: 2013-2024Crossref PubMed Scopus (0) Google Scholar Low-intensity production of ROS is important in metabolic adaptation, moderate ROS release may be involved in regulating inflammatory mediators, and high levels of ROS activate pathways, such as apoptosis or autophagy. In each case, different H2O2-sensitive pathways are mobilized.27Finkel T. Signal transduction by mitochondrial oxidants.J Biol Chem. 2012; 287: 4434-4440Crossref PubMed Scopus (164) Google Scholar, 28Meakin P.J. Chowdhry S. Sharma R.S. et al.Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance.Mol Cell Biol. 2014; 34: 3305-3320Crossref PubMed Google Scholar, 29Win S. Than T.A. Zhang J. et al.New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases.Hepatology. 2018; 67: 2013-2024Crossref PubMed Scopus (0) Google Scholar Mitochondria-derived ROS activate adenosine monophosate–activated protein kinase (AMPK)26Herzig S. Shaw R.J. AMPK: guardian of metabolism and mitochondrial homeostasis.Nat Rev Mol Cell Biol. 2018; 19: 121-135Crossref PubMed Scopus (29) Google Scholar, 28Meakin P.J. Chowdhry S. Sharma R.S. et al.Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance.Mol Cell Biol. 2014; 34: 3305-3320Crossref PubMed Google Scholar and mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK).29Win S. Than T.A. Zhang J. et al.New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases.Hepatology. 2018; 67: 2013-2024Crossref PubMed Scopus (0) Google Scholar Their substrate phosphorylation has direct consequences on diverse metabolic pathways, regulation of gene expression by transcription factors, and direct activation or inhibition of specific target proteins, such as protein tyrosine phosphatases and protein kinases. AMPK and MAPK signaling pathways are activated in response to different stresses, including alterations in nutrients, cytokines, growth factors, drugs, and toxins—these signaling pathways have important roles in development of liver diseases and injuries, such as NAFLD, ALD, viral hepatitis, fibrosis, inflammation, carcinogenesis, and drug-induced hepatotoxicity.26Herzig S. Shaw R.J. AMPK: guardian of metabolism and mitochondrial homeostasis.Nat Rev Mol Cell Biol. 2018; 19: 121-135Crossref PubMed Scopus (29) Google Scholar, 28Meakin P.J. Chowdhry S. Sharma R.S. et al.Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not wit