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Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy

Ahuja, Preeti and Wanagat, Jonathan and Wang, Zhihua and Wang, Yibin and Liem, David A. and Ping, Peipei and Antoshechkin, Igor A. and Margulies, Kenneth B. and MacLellan, W. Robb (2013) Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy. Circulation, 127 (19). pp. 1957-1967. ISSN 0009-7322. PMCID PMC4236313. doi:10.1161/CIRCULATIONAHA.112.001219. https://resolver.caltech.edu/CaltechAUTHORS:20130625-134010913

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Abstract

Background—Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. Methods and Results—To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 versus nonfailing hearts, P<0.05 versus ICM). Conclusions—In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α–dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001219DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236313/PubMed CentralArticle
ORCID:
AuthorORCID
Antoshechkin, Igor A.0000-0002-9934-3040
Additional Information:© 2013 American Heart Association, Inc. Received July 5, 2012; accepted March 21, 2013. Published online before print April 15, 2013. We thank Dr Alan Garfinkel for his expert assistance with statistical analysis. Next generation sequencing was performed at Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech. Sources of Funding: This work was supported by the National Institutes of Health (HL70748 and HL080111 to Dr MacLellan and HL070079, HL103205 and HL098954 to Dr Wang). This work was supported by the American Federation for Aging Research, the UCLA Hartford Center of Excellence, and National Institute on Aging Grants K08 AG032873 and UCLA Older Americans Independence Center P30 AG028748 to Dr Wanagat.
Funders:
Funding AgencyGrant Number
NIHHL70748
NIHHL080111
NIHHL070079
NIHHL103205
NIHHL098954
American Federation for Aging ResearchUNSPECIFIED
UCLA Hartford Center of ExcellenceUNSPECIFIED
National Institute on AgingK08 AG032873
UCLA Older Americans Independence CenterP30 AG028748
Subject Keywords:cardiomyopathy, dilated; DNA, mitochondrial; heart failure; mitochondrial turnover
Issue or Number:19
PubMed Central ID:PMC4236313
DOI:10.1161/CIRCULATIONAHA.112.001219
Record Number:CaltechAUTHORS:20130625-134010913
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130625-134010913
Official Citation:Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy Preeti Ahuja, Jonathan Wanagat, Zhihua Wang, Yibin Wang, David A. Liem, Peipei Ping, Igor A. Antoshechkin, Kenneth B. Margulies, and W. Robb MacLellan Circulation. 2013;127:1957-1967, published online before print April 15 2013, doi:10.1161/CIRCULATIONAHA.112.001219
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39091
Collection:CaltechAUTHORS
Deposited By: John Wade
Deposited On:25 Jun 2013 21:16
Last Modified:09 Nov 2021 23:42

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