RT Journal Article
A1 Yu-Wai-Man, Patrick
A1 Lai-Cheong, Joey
A1 Borthwick, Gillian M.
A1 He, Langping
A1 Taylor, Geoffrey A.
A1 Greaves, Laura C.
A1 Taylor, Robert W.
A1 Griffiths, Philip G.
A1 Turnbull, Douglass M.
T1 Somatic Mitochondrial DNA Deletions Accumulate to High Levels in Aging Human Extraocular Muscles
JF Investigative Ophthalmology & Visual Science
JO Invest. Ophthalmol. Vis. Sci.
YR 2010
DO 10.1167/iovs.09-4660
VO 51
IS 7
SP 3347
OP 3353
SN 1552-5783
AB    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.    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.    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 ≤70%.    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.  
RD 3/3/2021
UL https://doi.org/10.1167/iovs.09-4660