Document Detail


Defective DNA replication impairs mitochondrial biogenesis in human failing hearts.
MedLine Citation:
PMID:  20339121     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 gamma 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-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.
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.
Authors:
Georgios Karamanlidis; Luigino Nascimben; Gregory S Couper; Prem S Shekar; Federica del Monte; Rong Tian
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-03-25
Journal Detail:
Title:  Circulation research     Volume:  106     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-14     Completed Date:  2010-06-02     Revised Date:  2011-09-26    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1541-8     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of Washington, Seattle, WA, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
DNA Replication*
DNA, Mitochondrial / biosynthesis*,  genetics
Down-Regulation
Female
Heart Failure / genetics*,  pathology*
Heat-Shock Proteins / genetics,  metabolism
Humans
Male
Middle Aged
Mitochondria / genetics*,  pathology*
Transcription Factors / genetics,  metabolism
Young Adult
Grant Support
ID/Acronym/Agency:
R01 HL059246-10A1/HL/NHLBI NIH HHS; R01 HL067970-08/HL/NHLBI NIH HHS; R01 HL088634-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; 0/Heat-Shock Proteins; 0/PPARGC1A protein, human; 0/Transcription Factors
Comments/Corrections

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