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Cardiovascular Research 2003 57(1):147-157; doi:10.1016/S0008-6363(02)00695-8
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy

Dekui Zhanga, Justin L. Motta, Patricia Farrarb, Jan S. Ryersec, Shin-Wen Changa, Melissa Stevensa, Grace Dennigera and Hans Peter Zassenhausa,*

aDepartment of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA
bDepartment of Comparative Medicine, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA
cDepartment of Pathology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA

* Corresponding author. Tel.: +1-314-577-8444; fax: +1-314-773-3403. zassenp{at}slu.edu

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. Conclusion: mtDNA mutations therefore are pathogenic, and seem to trigger apoptosis through the mitochondrial pathway.

KEYWORDS Aging; Apoptosis; Cardiomyopathy; Mitochondria; Sequence (DNA/RNA/prot)


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