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

Koczor, Christopher A.; Torres, Rebecca A.; Fields, Earl; Boyd, Amy; He, Stanley; Patel, Nilamkumar; Lee, Eva K.; Samarel, Allen M.; Lewis, William

doi:10.1152/physiolgenomics.00014.2013

Cited by 20 publications

(12 citation statements)

References 44 publications

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“…Some genetic models implicate higher PKC␣ activity in hypertrophic CM, while others suggest it plays no role (2,3,13). Our data support a decreased expression of PKC␣ in AZT-induced CM, though as we have seen in our previous studies, there may be additional regulation of protein activity posttranscriptionally (19).…”

Section: Discussionsupporting

confidence: 84%

“…Our own studies and those of others have implicated changes in DNA methylation in the etiology of heart failure (17,19,(31)(32)(33). Because mitochondrial dysfunction has been observed in human congestive heart failure, a mechanism similar to the one observed here for altering DNA methylation may play a key role in human disease.…”

Section: Discussionsupporting

confidence: 69%

“…Methylation of cytosine in CpG results from activity of DNA methyltransferases that use S-adenosylmethionine (SAM) as the requisite methyl donor. We and others previously showed that changes in cardiac DNA methylation in CM correlate with gene expression changes (17,19,(31)(32)(33). Moreover, CM in humans is associated with mitochondrial dysfunction and oxidative stress, which are characteristics of AZT toxicity and are documented in murine studies (15,16,18,23).…”

mentioning

confidence: 84%

“…Gene expression was analyzed as previously described (17,19). RNA was extracted from hearts from at least three mice in each treatment group with the Qiagen Fibrous Tissue RNeasy kit (Qiagen, Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

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AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

Koczor

Jing

Fields

et al. 2015

Physiological Genomics

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Koczor CA, Jiao Z, Fields E, Russ R, Ludaway T, Lewis W. AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress. Physiol Genomics 47: 447-454, 2015. First published July 21, 2015 doi:10.1152/physiolgenomics.00045.2015.-Mitochondrial dysfunction causes oxidative stress and cardiomyopathy. Oxidative stress also is a side effect of dideoxynucleoside antiretrovirals (NRTI) and is observed in NRTI-induced cardiomyopathy. We show here that treatment with the NRTI AZT {1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione} modulates cardiac gene expression epigenetically through production of mitochondrially derived reactive oxygen species. Transgenic mice with ubiquitous expression of mitochondrially targeted catalase (MCAT) and C57Bl/6 wild-type mice littermates (WT) were administered AZT (0.22 mg/day po, 35 days), and cardiac DNA and mRNA were isolated. In AZT-treated WT, 95 cardiac genes were differentially expressed compared with vehicle-treated WTs. When MCAT mice were treated with AZT, each of those 95 genes reverted toward the expression of vehicle-treated WTs. In AZT-treated WT hearts, Mthfr [5,10-methylenetetrahydrofolate reductase; a critical enzyme in synthesis of methionine cycle intermediates including S-adenosylmethionine (SAM)], was overexpressed. Steady-state abundance of SAM in cardiac extracts from AZT-treated MCAT mice increased 60% above that of vehicle-treated MCAT. No such change occurred in WT. AZT caused hypermethylation (47%) and hypomethylation (53%) of differentially methylated DNA regions in WT cardiac DNA. AZTtreated MCAT heart DNA exhibited greater hypermethylation (91%) and less hypomethylation (9%) compared with vehicle-treated MCAT controls. The gene encoding protein kinase C-␣ displayed multifocal epigenetic regulation caused by oxidative stress. Results show that mitochondrially derived oxidative stress in the heart hinders cardiac DNA methylation, alters steady-state abundance of SAM, alters cardiac gene expression, and promotes characteristic pathophysiological changes of cardiomyopathy. This mechanism for NRTI toxicity offers insight into long-term side effects from these commonly used antiviral agents.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 69%

mentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

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AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

Koczor

Jing

Fields

et al. 2015

Physiological Genomics

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“…These validated targets are most likely involved in modifying DCM rather than independently causing disease. Furthermore, other authors found differentially methylated gene promoters and a depletion of mitochondrial DNA that resulted in a thymidine kinase deficiency in DCM hearts [61,62]. Indeed, investigating epigenetic mechanisms represents an attractive approach for finding novel mechanisms of disease.…”

Section: Molecular Basis Of Dilated Cardiomyopathy: Past and New Actorsmentioning

confidence: 99%

Idiopathic Dilated Cardiomyopathy: Molecular Basis and Distilling Complexity to Advance

Roura¹,

Gálvez‐Montón²,

Lupón³

et al. 2017

Cardiomyopathies - Types and Treatments

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Cardiomyopathies are heterogeneous diseases of the myocardium associated with abnormal findings of chamber size, wall thickness, and/or functional contractility. In particular, dilated cardiomyopathy (DCM) is mainly characterized by ventricular chamber enlargement with systolic dysfunction and normal left ventricular (LV) wall thickness. Although DCM is thought to be induced mainly by genetic or environmental factors, in the majority of cases, the cause is unknown. With an estimated prevalence of 1:2500 and an incidence of 1:18,000 per year in adults, DCM is the most frequent indication for heart transplantation, which represents an enormous cost burden on healthcare systems. These figures warrant greater accuracy in patient diagnosis and prognosis and further insight into the underlying basis of DCM. Here, we discuss past and recent findings on the molecular mechanisms involved in DCM. Dilated cardiomyopathy has been linked to the overactivation of extracellular signal-regulated kinase (ERK1/2), which in turn is related to activation of low-density lipoprotein receptorrelated protein-1 (LRP-1). Moreover, a redistribution of LRP-1 into cholesterol-enriched plasma membrane domains (lipid rafts) and alterations in cardiac DNA methylation have been reported in failing hearts. In conclusion, more comprehensive analyses of myocardial lipid rafts and epigenetic mechanisms may advance our understanding of DCM causes and progression. In turn, this understanding may promote the development of innovative treatments.

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Mitophagy plays a central role in mitochondrial ageing

2016

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The mechanisms underlying ageing have been discussed for decades, and advances in molecular and cell biology of the last three decades have accelerated research in this area. Over this period, it has become clear that mitochondrial function, which plays a major role in many cellular pathways from ATP production to nuclear gene expression and epigenetics alterations, declines with age. The emerging concepts suggest novel mechanisms, involving mtDNA quality, mitochondrial dynamics or mitochondrial quality control. In this review, we discuss the impact of mitochondria in the ageing process, the role of mitochondria in reactive oxygen species production, in nuclear gene expression, the accumulation of mtDNA damage and the importance of mitochondrial dynamics and recycling. Declining mitophagy (mitochondrial quality control) may be an important component of human ageing.

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

Cited by 20 publications

References 44 publications

AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress

Idiopathic Dilated Cardiomyopathy: Molecular Basis and Distilling Complexity to Advance

Mitophagy plays a central role in mitochondrial ageing

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