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Circ Res. 2010 May 14;106(9):1541-8. doi: 10.1161/CIRCRESAHA.109.212753. Epub 2010 Mar 25.

Defective DNA replication impairs mitochondrial biogenesis in human failing hearts.

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  • 1Department of Medicine, University of Washington, Seattle, WA, USA.



Mitochondrial dysfunction plays a pivotal role in the development of heart failure. Animal studies suggest that impaired mitochondrial biogenesis attributable to downregulation of the peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 transcriptional pathway is integral of mitochondrial dysfunction in heart failure.


The study sought to define mechanisms underlying the impaired mitochondrial biogenesis and function in human heart failure.


We collected left ventricular tissue from end-stage heart failure patients and from nonfailing hearts (n=23, and 19, respectively). The mitochondrial DNA (mtDNA) content was decreased by >40% in the failing hearts, after normalization for a moderate decrease in citrate synthase activity (P<0.05). This was accompanied by reductions in mtDNA-encoded proteins (by 25% to 80%) at both mRNA and protein level (P<0.05). The mRNA levels of PGC-1alpha/beta and PRC (PGC-1-related coactivator) were unchanged, whereas PGC-1alpha protein increased by 58% in the failing hearts. Among the PGC-1 coactivating targets, the expression of estrogen-related receptor alpha and its downstream genes decreased by up to 50% (P<0.05), whereas peroxisome proliferator-activated receptor alpha and its downstream gene expression were unchanged in the failing hearts. The formation of D-loop in the mtDNA was normal but D-loop extension, which dictates the replication process of mtDNA, was decreased by 75% in the failing hearts. Furthermore, DNA oxidative damage was increased by 50% in the failing hearts.


Mitochondrial biogenesis is severely impaired as evidenced by reduced mtDNA replication and depletion of mtDNA in the human failing heart. These defects are independent of the downregulation of the PGC-1 expression suggesting novel mechanisms for mitochondrial dysfunction in heart failure.

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