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

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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.", "claims": [{"id": "claim-target-result", "statement": "DCM left-ventricular mtDNA was depleted by 50% (P < 0.05); abundance was analyzed by qPCR, and methylation and gene-expression data were accessed through GEO accession GSE43435.", "kind": "quantitative", "target": {"value": 50.0, "unit": "per cent", "tolerance": null, "source": "LV mtDNA was depleted in DCM (50%, P < 0.05 each) compared with NF."}, "evidence": [{"asset": "source:pmid:23695887", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "We analyzed abundance of mtDNA and nuclear DNA (nDNA) using qPCR."}, {"asset": "source:pmid:23695887", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "LV mtDNA was depleted in DCM (50%, P < 0.05 each) compared with NF."}, {"asset": "source:pmid:23695887", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "DNA methylation and gene expression were determined using microarray analysis (GEO accession number: GSE43435)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "DCM left-ventricular mtDNA was depleted by 50% (P < 0.05); abundance was analyzed by qPCR, and methylation and gene-expression data were accessed through GEO accession GSE43435.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:23695887"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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