An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice

Mansouri, Abdellah; Gaou, Isabelle; Kerguenec, Caroline de; Amsellem, Sabine; Haouzi, D.; Berson, Alain; Moreau, Alain; Feldmann, Gérard; Lettéron, Philippe; Pessayre, Dominique; Fromenty, Bernard

doi:10.1016/s0016-5085(99)70566-4

Cited by 184 publications

(203 citation statements)

References 49 publications

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“…However, as mitochondria do not possess the nucleotide excision repair pathway, damaged mtDNA molecules harboring numerous strand breaks and/or bulky adducts may be preferentially degraded by mitochondrial endonucleases thus leading to mtDNA depletion. 20,36,40 Noteworthy, mtDNA pools were restored 24 h after CCl 4 or ethanol administration, 38 suggesting the presence of compensation and reparation processes in the liver. This rapid adaptive response could restrain the toxic consequences of CCl 4 induces early mitochondrial alterations L Knockaert et al mtDNA lesions after a single administration of CCl 4 or ethanol whereas a repeat exposure could induce the accumulation of damaged mtDNA molecules, inhibiting the resynthesis and inducing prolonged mtDNA depletion.…”

Section: Discussionmentioning

confidence: 96%

“…20,35,36 Previous studies on acute ethanol intoxication in mice reported a rapid fall of hepatic mtDNA levels which could be, at least in part, related to lipid peroxidation. [37][38][39] Thus both ethanol and CCl 4 induce lipid peroxidation and mtDNA depletion 2 or 3 h following their administration. The mechanisms by which mitochondrial genome lesions induced by lipid peroxidation (adducts, oxidized bases or single strand breaks) could cause mtDNA degradation and depletion are not well understood.…”

Section: Discussionmentioning

confidence: 99%

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Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Knockaert

Berson

Ribault

et al. 2012

Laboratory Investigation

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109

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Although carbon tetrachloride (CCl 4 )-induced acute and chronic hepatotoxicity have been extensively studied, little is known about the very early in vivo effects of this organic solvent on oxidative stress and mitochondrial function. In this study, mice were treated with CCl 4 (1.5 ml/kg ie 2.38 g/kg) and parameters related to liver damage, lipid peroxidation, stress/defense and mitochondria were studied 3 h later. Some CCl 4 -intoxicated mice were also pretreated with the cytochrome P450 2E1 inhibitor diethyldithiocarbamate or the antioxidants Trolox C and dehydroepiandrosterone. CCl 4 induced a moderate elevation of aminotransferases, swelling of centrilobular hepatocytes, lipid peroxidation, reduction of cytochrome P4502E1 mRNA levels and a massive increase in mRNA expression of heme oxygenase-1 and heat shock protein 70. Moreover, CCl 4 intoxication induced a severe decrease of mitochondrial respiratory chain complex IV activity, mitochondrial DNA depletion and damage as well as ultrastructural alterations. Whereas DDTC totally or partially prevented all these hepatic toxic events, both antioxidants protected only against liver lipid peroxidation and mitochondrial damage. Taken together, our results suggest that lipid peroxidation is primarily implicated in CCl 4 -induced early mitochondrial injury. However, lipid peroxidation-independent mechanisms seem to be involved in CCl 4 -induced early hepatocyte swelling and changes in expression of stress/defense-related genes. Antioxidant therapy may not be an efficient strategy to block early liver damage after CCl 4 intoxication.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Knockaert

Berson

Ribault

et al. 2012

Laboratory Investigation

Self Cite

109

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“…Long-range PCR was used to co-amplify long and short mtDNA fragments. 13 The PCR products were electrophoresed on 1% agarose gels and stained with ethidium bromide to visualize the 8636-bp and 316-bp DNA products. Band intensity was measured with a PhosphorImager (Molecular Dynamics, Sunnyvale, CA, USA), and the ratio of long to short DNA fragments was calculated.…”

Section: Quantitative Rt-pcr Of Mitochondrial Mrna Expressionmentioning

confidence: 99%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2 0 -deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.

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“…Fragmentation of mtDNA in renal tissues, possibly related to oxidative stress, was evaluated by PCR (9). Random DNA lesions are more likely to hamper the progression of the polymerase and decrease PCR amplification for long DNA fragments than short fragments.…”

Section: Amelioration Of Renal Injury and Extended Life Span By Klothmentioning

confidence: 99%

Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Haruna

Kashihara

Satoh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

224

212

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Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was Ϸ30% in ICGN mice, and Ϸ70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in ␤-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.aging ͉ glomerulonephritis ͉ oxidative stress ͉ tubular interstitial disease T he Klotho gene was originally identified by insertional mutagenesis, and it encodes a 130-kDa transmembrane protein that shares sequence homology with ␤-glucosidase (1). The gene is predominantly expressed in the kidney and, to a lesser extent, in the brain and reproductive and endocrine organs. Its deletion in mice (Kl Ϫ/Ϫ ) results in the development of a syndrome resembling human aging, including shortened life span, growth retardation, infertility, arteriosclerosis, skin and muscle atrophy, osteoporosis, and pulmonary emphysema (1). Conversely, overexpression of the Klotho gene extends the life span in mice (2). Although kl Ϫ/Ϫ mice do not show any overt renal abnormalities, the Klotho mRNA expression in the kidneys has been shown to be greatly reduced in patients with chronic renal failure (3). Notably, most of the features of Klotho gene-deleted mice are similar to those of the patients with chronic renal failure. In addition, Klotho gene expression has been found to be reduced in acute renal failure in ischemia-reperfusion injury murine models (4). These findings would imply that the reduction of Klotho protein may be relevant to the pathophysiology of renal failure. However, little is known concerning whether Klotho protein itself could exert an ameliorative effect on a diseased kidney to preserve its renal functions and thus could serve as a therapeutic target in various ...

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An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice

Cited by 184 publications

References 49 publications

Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Amelioration of progressive renal injury by genetic manipulation of Klotho gene

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