Lauritzen 2015 Am J Physiol Heart Circ Physiol
|Lauritzen KH, Kleppa L, Aronsen JM, Eide L, Carlsen H, Haugen ØP, Sjaastad I, Klungland A, Rasmussen LJ, Attramadal H, Storm-Mathisen J, Bergersen LH (2015) Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure. Am J Physiol Heart Circ Physiol 309:H434-49.|
Abstract: Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized, mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ∼2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1α, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease.
• Keywords: Tet-on, Cardiomyopathy, Heart failure, Mitochondrial dynamics, Mitochondrial function, mtDNA, Frozen heart homogenate
• O2k-Network Lab: NO Oslo Eide L
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mt-Structure;fission;fusion, mtDNA;mt-genetics, Genetic knockout;overexpression, Pharmacology;toxicology Pathology: Cardiovascular
Organism: Mouse Tissue;cell: Heart Preparation: Homogenate
Pathway: S HRR: Oxygraph-2k