Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients

Mansouri, Abdellah; Fromenty, Bernard; Berson, Alain; Robin, Marie-Anne; Grimbert, Sylvie; Beaugrand, Michel; Erlinger, S; Pessayre, Dominique

doi:10.1016/s0168-8278(97)80286-3

Cited by 133 publications

(106 citation statements)

References 19 publications

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“…Factors affecting the efficiency of NADH oxidation by the mitochondria have also been proposed to contribute to the metabolic imbalances responsible for hepatic steatosis . Supporting this view, mitochondrial DNA deletions show a very high prevalence (about 85% of the cases) in patients with alcoholism who have hepatic microvesicular steatosis Mansouri et al 1997), which is a lesion that is ascribed to impaired mitochondrial b-oxidation of fatty acids . Although supplementation with antioxidants such as ebselen, polyphenolic extracts or allopurinol (Arteel, 2003), but not with the 21-aminosteroid, tirilazad mesylate and N-acetlycysteine (Sadrzadeh & Nanji, 1998;Ronis et al 2005), ameliorates the fat accumulation induced by enteral feeding of alcohol, the mechanisms involved have not been clarified.…”

Section: Oxidative Mechanisms and Mitochondrial Damage By Ethanolmentioning

confidence: 85%

“…Mitochondria obtained from both acute and chronic alcohol-treated rats show oxidative modifications of mitochondrial DNA (Hoek et al 2002). Single or multiple deletions of mitochondrial DNA are also 8-fold more frequent in the liver of patients with alcoholism as compared with age-matched controls (Mansouri et al 1997). These alterations are probably responsible for the reduction in mitochondriallyencoded subunits of the electron transport chain observed in experimental animals following chronic ethanol treatment, and together with the alkylation of cytochrome c oxidase by lipid peroxidation products they contribute to the impairment of hepatic respiratory activity caused by alcohol (Bailey & Cunningham, 2002).…”

Section: Oxidative Mechanisms and Mitochondrial Damage By Ethanolmentioning

confidence: 99%

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Alcohol, oxidative stress and free radical damage

2006

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The involvement of free radical mechanisms in the pathogenesis of alcoholic liver disease (ALD) is demonstrated by the detection of lipid peroxidation markers in the liver and the serum of patients with alcoholism, as well as by experiments in alcohol-feed rodents that show a relationship between alcohol-induced oxidative stress and the development of liver pathology. Ethanol-induced oxidative stress is the result of the combined impairment of antioxidant defences and the production of reactive oxygen species by the mitochondrial electron transport chain, the alcohol-inducible cytochrome P450 (CYP) 2E1 and activated phagocytes. Furthermore, hydroxyethyl free radicals (HER) are also generated during ethanol metabolism by CYP2E1. The mechanisms by which oxidative stress contributes to alcohol toxicity are still not completely understood. The available evidence indicates that, by favouring mitochondrial permeability transition, oxidative stress promotes hepatocyte necrosis and/or apoptosis and is implicated in the alcohol-induced sensitization of hepatocytes to the pro-apoptotic action of TNF-a. Moreover, oxidative mechanisms can contribute to liver fibrosis, by triggering the release of pro-fibrotic cytokines and collagen gene expression in hepatic stellate cells. Finally, the reactions of HER and lipid peroxidation products with hepatic proteins stimulate both humoral and cellular immune reactions and favour the breaking of self-tolerance during ALD. Thus, immune responses might represent the mechanism by which alcohol-induced oxidative stress contributes to the perpetuation of chronic hepatic inflammation. Together these observations provide a rationale for the possible clinical application of antioxidants in the therapy for ALD.

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Section: Oxidative Mechanisms and Mitochondrial Damage By Ethanolmentioning

confidence: 85%

Section: Oxidative Mechanisms and Mitochondrial Damage By Ethanolmentioning

confidence: 99%

Alcohol, oxidative stress and free radical damage

2006

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“…Ethanol induced hepatic mtDNA depletion after a single binge in mice (Demeilliers et al, 2002), or chronic ethanol intoxication in aged rats (Cederbaum, 1999). Multiple hepatic mtDNA deletions were frequently observed in the liver tissue and white blood cells (WBC) obtained from patients with alcoholic liver disease (ALD) (Mansouri et al, 1997). Together, these results suggest that ethanol intoxication might induce a decrease in the copy number of mtDNA and an increase in the proportion of mtDNA deletion in the liver tissues of male HCC patients.…”

Section: Discussionmentioning

confidence: 96%

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma

Yin¹,

Lee

Chau³

et al. 2004

Br J Cancer

192

158

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Somatic mutations in mitochondrial DNA (mtDNA) have been detected in hepatocellular carcinoma (HCC). However, it remains unclear whether mtDNA copy number and mitochondrial biogenesis are altered in HCC. In this study, we found that mtDNA copy number and the content of mitochondrial respiratory proteins were reduced in HCCs as compared with the corresponding nontumorous livers. MtDNA copy number was significantly reduced in female HCC but not in male HCC. Expression of the peroxisome proliferator-activated receptor g coactivator-1 was significantly repressed in HCCs (Po0.005), while the expression of the mitochondrial single-strand DNA-binding protein was upregulated, indicating that the regulation of mitochondria biogenesis is disturbed in HCC. Moreover, 22% of HCCs carried a somatic mutation in the mtDNA D-loop region. The non-tumorous liver of the HCC patients with a long-term alcohol-drinking history contained reduced mtDNA copy number (Po0.05) and higher level of the 4977 bp-deleted mtDNA (Po0.05) as compared with non-alcohol patients. Our results suggest that reduced mtDNA copy number, impaired mitochondrial biogenesis and somatic mutations in mtDNA are important events during carcinogenesis of HCC, and the differential alterations in mtDNA of male and female HCC may contribute to the differences in the clinical manifestation between female and male HCC patients.

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“…Though our data display a great variability even in individuals of the same age group, the large pool of data may help to discriminate between physiological ageing and pathological conditions associated with accelerated ageing. Interestingly an increase in deletion amounts is observed in association with smoking (Ballinger et al, 1996), ethanol consumption (Mansouri et al, 1997) or sunlight exposure (Ray et al, 2000), all of which seem to accelerate the ageing process. There are at least three aspects that render the deletion an excellent biomarker.…”

Section: Discussionmentioning

confidence: 99%

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

Meißner

Bruse

Mohamed

et al. 2008

Experimental Gerontology

144

119

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It has been suggested that deletions of mitochondrial DNA (mtDNA) are important players with regard to the ageing process. Since the early 1990s, the 4977 bp deletion has been studied in various tissues, especially in postmitotic tissues with high energy demand. Unfortunately, some of these studies included less than 10 subjects, so the aim of our study was to quantify reliable the deletion amount in nine different regions of human brain, heart and skeletal muscle in a cohort of 92 individuals. The basal ganglia contain the highest deletion amounts with values up to 2.93% and differences in deletion levels between early adolescence and older ages were up to three orders of magnitude. Values in frontal lobe were on average an order of magnitude lower, but lowest in cerebellar tissue where the amount was on average only 5 x 10 -3 of the basal ganglia. The deletion started to accumulate in iliopsoas muscle early in the fourth decade of life with values between 0.00019% and 0.0035% and was highest in a 102 year-old woman with 0.14%. In comparison to skeletal muscle, the overall abundance in heart muscle of the left ventricle was only one third. The best linear logarithmic correlation between amount of the deletion and age was found in substanta nigra with r=0.87 (p<0.0005) followed by anterior wall of the left ventricle (r=0.82; p<0.0005). With regard to mitochondrial DNA damage, we propose to use the 4977 bp deletion as an ideal biomarker to discriminate between physiological ageing and accelerated ageing. The biological meaning of mitochondrial deletions in the process of ageing is under discussion, but there is experimental evidence that large-scale deletions impair the oxidative phosphorylation in single cells and sensitize these cells to undergo apoptosis.

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Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients

Cited by 133 publications

References 19 publications

Alcohol, oxidative stress and free radical damage

Alcohol, oxidative stress and free radical damage

Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

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