ArticlePhysiological genomics2013
Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation.
Article in Physiological genomics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Strand displacement-triggered FRET nanoprobe tracking TK1 mRNA in living cells for ratiometric fluorimetry of nucleic acid biomarker.Mikrochimica acta · 2024Article
- Identification of Signature Genes of Dilated Cardiomyopathy Using Integrated Bioinformatics Analysis.International journal of molecular sciences · 2023Article
- Methylation status of TK1 correlated with immune infiltrates in prostate cancer.Frontiers in genetics · 2022Article
- Proliferation PET tracerJournal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology · 2021Article
- Mitophagy plays a central role in mitochondrial ageing.Mammalian genome : official journal of the International Mammalian Genome Society · 2016Review
- Mitochondrial polymerase gamma dysfunction and aging cause cardiac nuclear DNA methylation changes.Physiological genomics · 2016Article
- Methamphetamine and HIV-Tat alter murine cardiac DNA methylation and gene expression.Toxicology and applied pharmacology · 2015Article
- AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress.Physiological genomics · 2015Article
- An uncommon clinical presentation of relapsing dilated cardiomyopathy with identification of sequence variations in MYNPC3, KCNH2 and mitochondrial tRNA cysteine.Molecular genetics and metabolism reports · 2015Article
- The emergence of the mitochondrial genome as a partial regulator of nuclear function is providing new insights into the genetic mechanisms underlying age-related complex disease.Human genetics · 2014Review
- On form and function: does chromatin packing regulate the cell cycle?Physiological genomics · 2014Article
- Detection of differentially methylated gene promoters in failing and nonfailing human left ventricle myocardium using computation analysis.Physiological genomics · 2013Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
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 = 18) were obtained fresh at heart transplant surgery. Parallel samples from nonfailing (NF) controls (n = 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 < 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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