Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart

Lemieux, Hélène; Semsroth, Severin; Antretter, Herwig; Höfer, Daniel; Gnaiger, Erich

doi:10.1016/j.biocel.2011.08.008

Cited by 159 publications

(155 citation statements)

References 55 publications

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“…The mean age (Ϯ SE) of NF mtDNA abundance. Reduction of cardiomyocytic energy production leads to cardiac dysfunction and heart failure in mouse models, and its reduction in human DCM required further exploration (22,25,26). Clinical data support the role of decreased OXPHOS and ATP production in heart failure (35,43).…”

Section: Resultsmentioning

confidence: 99%

Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation

Koczor

Torres

Fields

et al. 2013

Physiological Genomics

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Koczor CA, Torres RA, Fields EJ, Boyd A, He S, Patel N, Lee EK, Samarel AM, Lewis W. Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation. Physiol Genomics 45: 590 -596, 2013. First published May 21, 2013 doi:10.1152/physiolgenomics.00014.2013.-This study addresses how depletion of human cardiac left ventricle (LV) mitochondrial DNA (mtDNA) and epigenetic nuclear DNA methylation promote cardiac dysfunction in human dilated cardiomyopathy (DCM) through regulation of pyrimidine nucleotide kinases. Samples of DCM LV and right ventricle (n ϭ 18) were obtained fresh at heart transplant surgery. Parallel samples from nonfailing (NF) controls (n ϭ 12) were from donor hearts found unsuitable for clinical use. We analyzed abundance of mtDNA and nuclear DNA (nDNA) using qPCR. LV mtDNA was depleted in DCM (50%, P Ͻ 0.05 each) compared with NF. No detectable change in RV mtDNA abundance occurred. DNA methylation and gene expression were determined using microarray analysis (GEO accession number: GSE43435). Fifty-seven gene promoters exhibited DNA hypermethylation or hypomethylation in DCM LVs. Among those, cytosolic thymidine kinase 1 (TK1) was hypermethylated. Expression arrays revealed decreased abundance of the TK1 mRNA transcript with no change in transcripts for other relevant thymidine metabolism enzymes. Quantitative immunoblots confirmed decreased TK1 polypeptide steady state abundance. TK1 activity remained unchanged in DCM samples while mitochondrial thymidine kinase (TK2) activity was significantly reduced. Compensatory TK activity was found in cardiac myocytes in the DCM LV. Diminished TK2 activity is mechanistically important to reduced mtDNA abundance and identified in DCM LV samples here. Epigenetic and genetic changes result in changes in mtDNA and in nucleotide substrates for mtDNA replication and underpin energy starvation in DCM.

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Section: Resultsmentioning

confidence: 99%

Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation

Koczor

Torres

Fields

et al. 2013

Physiological Genomics

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“…In clinical studies (6,26), ETS capacity exceeds OXPHOS capacity with complex Ior complex I ϩ II-linked substrates in cardiac and skeletal muscles. However, in the present study, ETS capacity did not exceed OXPHOS capacity with complex II-linked substrates in cardiac and skeletal muscles not only from control cats (8a) but also from HCM cats, suggesting that there was no excess capacity of the ETS in these muscles from cats.…”

Section: No Excess Capacity Of the Ets With Complex Ii-linked Substramentioning

confidence: 99%

Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy

Christiansen

Dela

Koch

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Yokota T. Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 308: H1237-H1247, 2015. First published March 13, 2015; doi:10.1152/ajpheart.00727.2014.-Mitochondrial dysfunction and oxidative stress are important players in the development of various cardiovascular diseases, but their roles in hypertrophic cardiomyopathy (HCM) remain unknown. We examined whether mitochondrial oxidative phosphorylation (OXPHOS) capacity was impaired with enhanced mitochondrial oxidative stress in HCM. Cardiac and skeletal muscles were obtained from 9 domestic cats with spontaneously occurring HCM with preserved left ventricular systolic function and from 15 age-matched control cats. Mitochondrial OXPHOS capacities with nonfatty acid and fatty acid substrates in permeabilized fibers and isolated mitochondria were assessed using high-resolution respirometry. ROS release originating from isolated mitochondria was assessed by spectrofluorometry. Thiobarbituric acid-reactive substances were also measured as a marker of oxidative damage. Mitochondrial ADP-stimulated state 3 respiration with complex I-linked nonfatty acid substrates and with fatty acid substrates, respectively, was significantly lower in the hearts of HCM cats compared with control cats. Mitochondrial ROS release during state 3 with complex I-linked substrates and thiobarbituric acid-reactive substances in the heart were significantly increased in cats with HCM. In contrast, there were no significant differences in mitochondrial OXPHOS capacity, mitochondrial ROS release, and oxidative damage in skeletal muscle between groups. Mitochondrial OXPHOS capacity with both nonfatty acid substrates and fatty acid substrates was impaired with increased mitochondrial ROS release in the feline HCM heart. These findings provide new insights into the pathophysiology of HCM and support the hypothesis that restoration of the redox state in the mitochondria is beneficial in the treatment of HCM. hypertrophic cardiomyopathy; mitochondria; oxidative stress

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“…SUIT protocols for the analysis of oxidative phosphorylation improve our understanding of mitochondrial respiratory control and the pathophysiology of mitochondrial diseases (Gnaiger, 2009;Pesta and Gnaiger, 2012). An early defect of oxidative phosphorylation in the failing human heart was demonstrated by HRR (Lemieux et al, 2011). In type 2 diabetes patients, Phielix et al (2008) showed, by using multiple substrates, that compromised mitochondrial function resides at the level of the phosphorylation system.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial function and aerobic capacity assessed by high resolution respirometry in Thoroughbred horses

Serteyn

Ceusters

Nonnenmacher

et al. 2016

CEP

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During the initial stages of training of young Thoroughbred horses, low intensity exercise is employed to increase aerobic capacity. High Resolution Respirometry (HRR) allows the determination of aerobic capacities in small samples of permeabilised muscle fibres. The aim of the study was to measure the mitochondrial function by HRR in Thoroughbred horses, to compare these values to Warmblood horses and to evaluate the effect of a 10-weeks training period. The mitochondrial function was measured by HRR using different substrate-uncoupler protocols (SUIT 1 and 2) in muscle microbiopsies from two groups of untrained horses: 17 Warmblood and 8 Thoroughbred and in the group of 8 Thoroughbred horses before and after a 10-week training period. The SUIT1 protocol employed to compare the two groups of horses showed that in Thoroughbred horses, the mean values for oxygen flux expressed as tissue mass-specific respiration were significantly higher for complex I (CI) Glutamate+Malate , CI + complex II, and maximum electron transport capacities (ETSmax) than the mean values measured in Warmblood horses. The SUIT 1 and SUIT 2 protocols revealed large differences among Thoroughbred horses before and after training. The SUIT 2 protocols showed a significant difference for the complex I activity before and after training but only when the oxygen flux was expressed as percentage of ETSmax. This study shows the interest of HRR in equine sport medicine and exercise physiology, but shows that the technique requires further refinement. Indeed significant differences have been shown between the Thoroughbred and the Warmblood horses highlighting the need to have baseline data for each breed. The Thoroughbred horses had globally a high oxidative phosphorylation capacity with an increase of CI activity induced by an aerobic training program.

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Mitochondrial respiratory control and early defects of oxidative phosphorylation in the failing human heart

Cited by 159 publications

References 55 publications

Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation

Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation

Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy

Mitochondrial function and aerobic capacity assessed by high resolution respirometry in Thoroughbred horses

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