| Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. | |
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MedLine Citation:
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PMID: 20339121 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Georgios Karamanlidis; Luigino Nascimben; Gregory S Couper; Prem S Shekar; Federica del Monte; Rong Tian |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-03-25 |
Journal Detail:
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Title: Circulation research Volume: 106 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-14 Completed Date: 2010-06-02 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1541-8 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Washington, Seattle, WA, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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0/DNA, Mitochondrial; 0/Heat-Shock Proteins; 0/PPARGC1A protein, human; 0/Transcription Factors |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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