Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation.
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.
Kohler
James J
JJ
Department of Pathology, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA. jjkohle@emory.edu
Hosseini
Seyed H
SH
Cucoranu
Ioan
I
Hoying-Brandt
Amy
A
Green
Elgin
E
Johnson
David
D
Wittich
Bree
B
Srivastava
Jaya
J
Ivey
Kristopher
K
Fields
Earl
E
Russ
Rodney
R
Raper
C Michael
CM
Santoianni
Robert
R
Lewis
William
W
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D023241:Antiretroviral Therapy, Highly Active; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000032:analysis / Q000378:metabolism*; D004452:Echocardiography; D005260:Female; D006352:Heart Ventricles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism; D019469:Indinavir / Q000633:toxicity; D019259:Lamivudine / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D015215:Zidovudine / Q000633:toxicity
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir; C105339:thymidine kinase 2; D013937:Thymidine Kinase