title: Mitochondrial DNA mutations activate programmed cell survival in the mouse heart.
abstract: Increased frequencies of mitochondrial DNA (mtDNA) mutations characterize the aging heart and are also found in idiopathic dilated cardiomyopathy and end-stage heart failure. The pathogenic potential of such mutations is unclear. Transgenic mice showing accelerated accumulation of mtDNA mutations and dilated cardiomyopathy due to expression of an error-prone mtDNA polymerase specifically in the heart were characterized by Western blot analysis and immunohistochemistry for the levels of pro- and antiapoptotic proteins. By 8 wk of age, when frequencies of mtDNA mutations were approximately 0.01% and all transgenic mice showed four-chamber cardiac dilation, a vigorous prosurvival response was evident. Upregulated were Bcl-2, Bcl-xl, Bfl1, heat shock protein 27, and X-linked inhibitor of apoptosis protein, all of which function to inhibit apoptosis. Although translocation of Bax to mitochondria was also seen, it was not integrated into the mitochondrial membrane. Treatment of transgenic mice with doxorubicin failed to induce apoptosis, in contrast to controls, showing that the prosurvival response protected cardiomyocytes from a death stimulus. Increased apoptosis and release of cytochrome c appeared to precede the establishment of the prosurvival state suggesting that it may reflect a response to activation of programmed cell death pathways. It has been proposed that a programmed cell survival response is activated in the failing and aging heart. We show that elevated frequencies of mtDNA mutations may serve as one trigger for the activation of such a response.
authors.affiliation: Saint Louis University Health Science Center, Department of Molecular Microbiology and Immunology, St. Louis, Missouri 63104, USA.
authors.forename: Dekui
authors.initials: D
authors.lastname: Zhang
authors.forename: Justin L
authors.initials: JL
authors.lastname: Mott
authors.forename: Shin-Wen
authors.initials: SW
authors.lastname: Chang
authors.forename: Melissa
authors.initials: M
authors.lastname: Stevens
authors.forename: Peter
authors.initials: P
authors.lastname: Mikolajczak
authors.forename: H Peter
authors.initials: HP
authors.lastname: Zassenhaus
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D055551:HSP27 Heat-Shock Proteins; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486699:Hspb2 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2