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Somatic mitochondrial DNA deletions accumulate to high levels in aging human extraocular muscles.

Abstract：

:PURPOSE. Mitochondrial function and the presence of somatic mitochondrial DNA (mtDNA) defects were investigated in extraocular muscles (EOMs) collected from individuals covering a wide age range, to document the changes seen with normal aging. METHODS. Cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry was performed on 46 EOM samples to determine the level of COX deficiency in serial cryostat muscle sections (mean age, 42.6 years; range, 3.0-96.0 years). Competitive three-primer and real-time PCR were performed on single-fiber lysates to detect and quantify mtDNA deletions. Whole-genome mitochondrial sequencing was also performed to evaluate the contribution of mtDNA point mutations to the overall mutational load. RESULTS. COX-negative fibers were seen in EOMs beginning in the third decade of life, and there was a significant age-related increase: <30 years, 0.05% (n = 17); 30 to 60 years, 1.94% (n = 13); and >60 years, 3.34% (n = 16, P = 0.0001). Higher levels of COX deficiency were also present in EOM than in skeletal muscle in all three age groups (P < 0.0001). Most of the COX-negative fibers harbored high levels (>70%) of mtDNA deletions (206/284, 72.54%) and the mean deletion level was 66.64% (SD 36.45%). The mutational yield from whole mitochondrial genome sequencing was relatively low (1/19, 5.3%), with only a single mtDNA point mutation identified among COX-negative fibers with low deletion levels < or =70%. CONCLUSIONS. The results show an exponential increase in COX deficiency in EOMs beginning in early adulthood, which suggests an accelerated aging process compared with other postmitotic tissues.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Yu-Wai-Man P,Lai-Cheong J,Borthwick GM,He L,Taylor GA,Greaves LC,Taylor RW,Griffiths PG,Turnbull DM

doi

10.1167/iovs.09-4660

subject

Has Abstract

pub_date

2010-07-01 00:00:00

pages

3347-53

issue

7

eissn

0146-0404

issn

1552-5783

pii

iovs.09-4660

journal_volume

51

pub_type

杂志文章

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