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Transgenic expression of mitochondrial thymidine kinase isoform (TK2) increases mitochondrial DNA (mtDNA) and subsequent myocardial dysfunction following HAART
Author(s) -
Hosseini Seyed,
Kohler James,
Haase Chad,
Ludaway Tomika,
Russ Rodney,
McNaught Jamie,
Tioleco Nina,
Keebaugh Erin,
Lewis William
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a639
Subject(s) - mitochondrial dna , gene isoform , mitochondrion , genetically modified mouse , microbiology and biotechnology , transgene , biology , genetics , gene
Two distinct thymidine kinase (TK) isoforms are found in mammalian cells: cytoplasmic (TK1) and mitochondrial (TK2). In addition to the native deoxyribonucleoside substrates, these kinases can phosphorylate a variety of antiviral prodrugs. In antiretroviral therapy TK1 and TK2 play key roles because they catalyze the first step in activation of nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs exhibit mitochondrial toxicity. Two transgenic lines were created that over‐expressed the human TK1 or TK2 gene in murine myocardium to decipher mechanisms of toxicity. HAART treatment (including zidovudine, lamivudine and indinavir) were administered by gavage to TG’s and wild type (WT) littermates (35 days) at human doses. Cardiac and mitochondrial structure and function were examined. Left ventricle (LV) mass was defined echocardiographically (ECHO), mitochondrial ultrastructural defects were identified by electron microscopy (EM), and abundance of cardiac mtDNA was quantified by real time PCR. TGs expressing TK1 had no changes in LV mass from WTs, with or without HAART. mtDNA levels also remained constant. In contrast, TGs expressing TK2 with HAART had significant increase in LV mass from WTs with HAART. Cardiac mtDNA significantly increased in TGs expressing TK2 with or without HAART, compared to WTs. Data here suggest that NRTI phosphorylation by TK2 over‐expression in the murine heart has a significant effect on mtDNA abundance compared to that of TK1 over‐expression. These data suggest that mitochondrial toxicity of NRTIs relates to pharmacological events within mitochondria. Research supported by NIH/NHLBI R01HL072707 and R01HL059798.