Impaired mtDNA replication precedes mtDNA depletion in pressure overload-induced cardiac hypertrophy and heart failure

Accumulating evidence indicates that mitochondrial dysfunction participates in the development of heart failure. However, there is limited knowledge about mtDNA changes during the progression from cardiac hypertrophy to heart failure. Transverse aortic constriction or sham operation was performed on 8-week-old mice to induce cardiac hypertrophy and heart failure as determined by echocardiographic analysis. Only the heart failure group exhibited a significant decrease in succinate dehydrogenase activity, mtDNA content normalized to nDNA, and the expression of mtDNA-encoded genes. However, down-regulation of the genes involved in the mtDNA replication fork exhibited an impairment of mtDNA replication in both stages following pressure overload. Significantly decreased expression levels of mRNA and protein of the PGC-1 pathway suggested that attenuation of this pathway might contribute to the impaired mitochondrial biogenesis and dysfunction in cardiac hypertrophy and heart failure. In conclusion, in our two-stage mouse model, depletion of mitochondrial mass and DNA content was only detected in the heart failure stage. The mtDNA replication and transcriptional regulation of mitochondrial biogenesis was determined to be down-regulated from an early stage following pressure overload.