Eliminating the Ant1 isoform produces a mouse with CPEO pathology but normal ocular motility.
OBJECTIVE
The adenine nucleotide transporter 1 gene (ANT1) encodes an inner mitochondrial membrane protein that transports ATP into the cell. Mutations within ANT1 produce a syndrome of chronic progressive external ophthalmoplegia (CPEO) in humans. Ant1 knockout (Ant1-/-) mice develop cardiomyopathy and mitochondrial myopathy of limb muscles. Because the extraocular muscles (EOM) are preferentially affected in human CPEO, the objective of this study was to determine whether Ant1-/- mice also exhibit an EOM mitochondrial myopathy.


METHODS
ANT isoform expression of isolated EOMs, EOM morphology and mitochondrial content, mitochondrial structure and function, ocular motility in intact mice, and contractile performance in isolated muscle preparations were examined.


RESULTS
Ant1-/- EOMs had the typical appearance of mitochondrial myopathy, including increase in mitochondrial size, number, and oxidative phosphorylation (OXPHOS) staining. However, there were no measurable ocular motor abnormalities in intact Ant1-/- mice, and their isolated EOMs did not show evidence of increased fatigability. EOMs of wild-type mice exhibited higher levels of Ant2 mRNA compared with hindlimb muscle, which may compensate for the Ant1 loss in mutant mouse EOMs and account for the normal EOM function.


CONCLUSIONS
The Ant1-/- mice provide a model in which to study CPEO pathology and compensatory mechanisms.
Yin
Hang
H
Atlanta VA Medical Center, Decatur, Georgia 30033, USA.
Stahl
John S
JS
Andrade
Francisco H
FH
McMullen
Colleen A
CA
Webb-Wood
Sarah
S
Newman
Nancy J
NJ
Biousse
Valerie
V
Wallace
Douglas C
DC
Pardue
Machelle T
MT
D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005133:Eye Movements; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008931:Mitochondria, Muscle / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000473:pathology; D009801:Oculomotor Muscles / Q000648:ultrastructure*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics* / Q000473:pathology*; D010085:Oxidative Phosphorylation; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
D033741:Adenine Nucleotide Translocator 1; D020033:Protein Isoforms; D012333:RNA, Messenger