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. © 2002 Published by Elsevier Science B.V. on behalf of European Society of Cardiology.
Zhang, D., Mott, J. L., Farrar, P., Ryerse, J. S., Chang, S. W., Stevens, M., … Zassenhaus, H. P. (2003). Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy. Cardiovascular Research, 57(1), 147–157. https://doi.org/10.1016/S0008-6363(02)00695-8