Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy.
OBJECTIVE
To determine whether low frequency mitochondrial DNA (mtDNA) mutations are pathogenic.


METHODS
We studied mice that express a proofreading-deficient mitochondrial DNA polymerase in the heart and develop cardiac mtDNA mutations.


RESULTS
At 4 weeks of age, when point mutation levels had risen to on average two per mitochondrial genome, these mice developed severe dilated cardiomyopathy. Interstitial fibrosis first became apparent at 4 weeks of age and progressed with age. Sporadic myocytic death occurred in all regions of the heart, apparently due to apoptosis as assessed by histological analysis and TUNEL staining. The frequency of TUNEL-positive cells peaked at 4-5 weeks of age and then gradually declined. While mitochondrial respiratory function, ultrastructure, and number remained normal, cytochrome c was released from mitochondria, a known apoptotic signal.


CONCLUSIONS
mtDNA mutations therefore are pathogenic, and seem to trigger apoptosis through the mitochondrial pathway.
Zhang
Dekui
D
Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
Mott
Justin L
JL
Farrar
Patricia
P
Ryerse
Jan S
JS
Chang
Shin-Wen
SW
Stevens
Melissa
M
Denniger
Grace
G
Zassenhaus
Hans Peter
HP
D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D003574:Cytochrome c Group / Q000378:metabolism; D004272:DNA, Mitochondrial; D005355:Fibrosis; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D017354:Point Mutation
D003574:Cytochrome c Group; D004272:DNA, Mitochondrial