Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients.
OBJECTIVE
A 4977-base pair deletion has been detected in the hepatic mitochondrial DNA of alcoholic patients with microvesicular steatosis, a lesion ascribed to impaired mitochondrial beta-oxidation. However, only a single deletion had been looked for in this previous study, and it could not be determined whether the deletion was preexisting or acquired. Alcohol abuse increases the formation of reactive oxygen species in hepatic mitochondria. If this effect accelerates the oxidative aging of mitochondrial DNA, several other mutations would be expected.


METHODS
The mtDNA region extending from nucleotide 8167 to nucleotide 14246 was screened for the presence of large mitochondrial DNA deletions in 58 alcoholic patients and 67 age-matched non-alcoholic controls. Hepatic DNA was subjected to polymerase chain reactions that amplified non-deleted and deleted mitochondrial DNA, respectively, and the boundaries of the mitochondrial DNA deletions were sequenced.


RESULTS
Only 3% of the non-alcoholic controls carried a mitochondrial DNA deletion, whereas 24% of all alcoholic patients and 85% of the 13 alcoholic patients with microvesicular steatosis exhibited either single or multiple 4977, 5385, 5039 and 5556-base pair mitochondrial DNA deletions. No deletion(s) were observed, however, in 13 patients with microvesicular steatosis due to other causes.


CONCLUSIONS
Diverse mitochondrial DNA rearrangements are observed in alcoholic patients with microvesicular steatosis. We suggest that alcohol abuse leads to premature oxidative aging of mitochondrial DNA. Hypothetically, oxidative damage to mitochondrial constituents (DNA, proteins and lipids) may favor microvesicular fat deposition.
Mansouri
A
A
INSERM Unité 24 and Centre de Recherche de Physiopathologie Hépatique(Association Claude Bernard), Hôpital Beaujon, Clichy, France.
Fromenty
B
B
Berson
A
A
Robin
M A
MA
Grimbert
S
S
Beaugrand
M
M
Erlinger
S
S
Pessayre
D
D
D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000437:Alcoholism / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion
D004272:DNA, Mitochondrial