Impaired adaptive resynthesis and prolonged depletion of hepatic mitochondrial DNA after repeated alcohol binges in mice

Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse 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. 7,20 In the present study, CCl 4 -induced early mtDNA depletion and damage were not associated with nDNA fragmentation, thus suggesting that mtDNA was specifically affected by lipid peroxidation products as previously described in vitro in isolated rat mitochondria. 29 An interesting observation in our study was CCl 4 -induced early reduction of CYP2E1 mRNA levels.…”

“…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.…”

“…The mitochondrial genome is more susceptible to oxidative damage than nDNA due to the absence of histone, incomplete DNA repair capacity and proximity to the mitochondrial respiratory chain, which is the main intracellular source of reactive oxygen species. 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.…”

“…19,20 Indeed, this technique is based on the rationale that randomly distributed blocking lesions are more likely to hamper amplification of a long stretch of mtDNA than a very short fragment. The selected primers (Table 1) allowed the amplification of a 317-bp mtDNA short fragment and a 6365-bp mtDNA long fragment.…”

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

“…It has been demonstrated that acute or chronic ethanol intoxication causes hepatic oxidative stress and mitochondrial dysfunction in human and experimental animals (Cederbaum, 1999). 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).…”