Defective DNA Replication Impairs Mitochondrial Biogenesis In Human Failing Hearts

Abstract

Rationale : 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 γ coactivator (PGC)-1 transcriptional pathway is integral of mitochondrial dysfunction in heart failure. Objective : The study sought to define mechanisms underlying the impaired mitochondrial biogenesis and function in human heart failure. Methods and Results : 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-1α/β and PRC (PGC-1–related coactivator) were unchanged, whereas PGC-1α protein increased by 58% in the failing hearts. Among the PGC-1 coactivating targets, the expression of estrogen-related receptor α and its downstream genes decreased by up to 50% ( P <0.05), whereas peroxisome proliferator-activated receptor α 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. Conclusions : 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.