Premature oxidative aging of hepatic mitochondrial DNA in Wilson's disease.
OBJECTIVE
Aging is associated with and may be caused by acquired somatic mutations of the mitochondrial genome. In Wilson's disease, inherited mutations of a nuclear gene encoding a copper transporter cause accumulation of copper in the liver, particularly within mitochondria. Because copper has prooxidant properties and the mitochondrial genome is particularly susceptible to oxidative damage, we hypothesized that Wilson's disease may cause premature oxidative aging of mitochondrial DNA.


METHODS
Hepatic DNA was screened for large mitochondrial DNA deletion(s) in 16 patients with Wilson's disease and 67 control subjects. Deleted mitochondrial DNA copies were amplified by polymerase chain reaction and were sequenced.


RESULTS
Although 15 of the 16 patients with Wilson's disease were 30 years old or younger, 8 of them (50%), including the 6 patients with cirrhosis (100%), had diverse mitochondrial DNA deletions, whereas only 2 controls (3%), aged 39 and 45 years, showed a mitochondrial DNA deletion.


CONCLUSIONS
Wilson's disease is associated with frequent, diverse, and early deletions of mitochondrial DNA. Accumulation of prooxidant copper within hepatic mitochondria may cause this premature oxidative aging of mitochondrial DNA. Thus, inherited mutations of a nuclear gene may cause somatic mutations of the mitochondrial genome in this condition.
Mansouri
A
A
INSERM Unité 24, Hôpital Beaujon, Clichy, France.
Gaou
I
I
Fromenty
B
B
Berson
A
A
Lettéron
P
P
Degott
C
C
Erlinger
S
S
Pessayre
D
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D001483:Base Sequence; D016009:Chi-Square Distribution; D003300:Copper / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D004247:DNA / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000032:analysis / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006527:Hepatolenticular Degeneration / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D010084:Oxidation-Reduction; D016133:Polymerase Chain Reaction
D004272:DNA, Mitochondrial; D017665:Hydroxyl Radical; D003300:Copper; D004247:DNA