MULTIPLE HEPATIC MITOCHONDRIAL-DNA DELETIONS SUGGEST PREMATURE OXIDATIVE AGING IN ALCOHOLIC PATIENTS

Background/Aims: A 4977-base pair deletion has been detected in the he patic mitochondrial DNA of alcoholic patients with microvesicular stea tosis, a lesion ascribed to impaired mitochondrial beta-oxidation. How ever, only a single deletion had been looked for in this previous stud y, 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 oxida tive aging of mitochondrial DNA, several other mutations would be expe cted. Methods: The mtDNA region extending from nucleotide 8167 to nucl eotide 14246 was screened for the presence of large mitochondrial DNA deletions in 58 alcoholic patients and 67 age-matched non-alcoholic co ntrols. Hepatic DNA was subjected to polymerase chain reactions that a mplified non-deleted and deleted mitochondrial DNA, respectively, and the boundaries of the mitochondrial DNA deletions were sequenced. Resu lts: Only 3% of the non-alcoholic controls carried a mitochondrial DNA deletion, whereas 24% of all alcoholic patients and 85% of the 13 alc oholic patients with microvesicular steatosis exhibited either single or multiple 4977, 5385, 5039 and 5556-base pair mitochondrial DNA dele tions. No deletion(s) were observed, however, in 13 patients with micr ovesicular steatosis due to other causes. Conclusions: Diverse mitocho ndrial DNA rearrangements are observed in alcoholic patients with micr o vesicular steatosis. We suggest that alcohol abuse leads to prematur e oxidative aging of mitochondrial DNA. Hypothetically, oxidative dama ge to mitochondrial constituents (DNA, proteins and lipids) may favor microvesicular fat deposition.