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. 2009 Feb;89(2):122-30.
doi: 10.1038/labinvest.2008.121. Epub 2008 Dec 15.

Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation

James J Kohler  1 , Seyed H Hosseini, Ioan Cucoranu, Amy Hoying-Brandt, Elgin Green, David Johnson, Bree Wittich, Jaya Srivastava, Kristopher Ivey, Earl Fields, Rodney Russ, C Michael Raper, Robert Santoianni, William Lewis
Affiliations

Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation

James J Kohler et al. Lab Invest. 2009 Feb.

Abstract

Mitochondrial toxicity results from pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS. In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) were generated to determine their individual impact on native mitochondrial biogenesis and effects of NRTI administration on development of mitochondrial toxicity. TGs included cardiac-specific overexpression of native thymidine kinase 2 (TK2), two pathogenic TK2 mutants (H121N and I212N), and a mutant of mtDNA polymerase, pol-gamma (Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs.

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Figures

Figure 1
Figure 1
Timeline of longitudinal studies. Treatment course is outlined with equivalent biological age indicated and overall range of maturation phase vs adulthood shown (based on Figure 2 data).
Figure 2
Figure 2
Temporal changes in mtDNA abundance during maturation to adult. Skeletal muscle and cardiac tissues (a and b, respectively) were collected from WT FVB/n cohorts at various end points in early age beginning at weeks 7–9 (youth) at intervals up to 26 weeks (adult).
Figure 3
Figure 3
Longitudinal changes in relative mtDNA abundance after AZT-HAART treatment initiation. Using ‘2 × 2’ protocols, four different TGs were treated with AZT-HAART or vehicle for 3 and 10 weeks duration (a and b, respectively) and mtDNA abundance levels from cardiac tissues were determined and compared to WT littermates.
Figure 4
Figure 4
Longitudinal cardiac hypertrophy development in TGs. Left ventricular mass (LV mass) was recorded for ‘2 × 2’ cohorts of TGs treated with AZT-HAART or vehicle at 3 and 10 weeks duration (a and b, respectively).
Figure 5
Figure 5
Longitudinal development of cardiac dilation in TGs. Left ventricular end-diastolic dimension (LVEDD) was determined for TGs and WTs treated with AZT-HAART or vehicle at 3 and 10 weeks duration (a and b, respectively).
Figure 6
Figure 6
Ultrastructural changes in cardiac mitochondrial tissues following 10 weeks of AZT-HAART. Cardiac tissues from all four TG cohorts treated with vehicle (a) or AZT-HAART (b) and WT littermates were compared using electron microscopy (EM, original magnification × 22 400).
Figure 7
Figure 7
Schematic summary of the impact of diverse mutant TGs of mtDNA replication pathway. Highlighted are the roles of native TK2 or TK2 mutants in the phosphorylation of nucleoside analogues (eg, AZT) and the role of pol-γ mutant (Y955C) in the incorporation of the active nucleoside triphosphate (eg, AZT-TP) in mtDNA replication. These constitute potential targets for inhibition of the mtDNA replication pathway.
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