Cardiac-targeted transgenic mutant mitochondrial enzymes: mtDNA defects, antiretroviral toxicity and cardiomyopathy.
Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs ( approximately 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass ( approximately 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.
Kohler
James J
JJ
Department of Pathology, Emory University School of Medicine, 7126 Woodruff Memorial Building, 101 Woodruff Circle, Atlanta, GA, 30322, USA. jjkohle@emory.edu
Hosseini
Seyed H
SH
Green
Elgin
E
Hoying-Brandt
Amy
A
Cucoranu
Ioan
I
Haase
Chad P
CP
Russ
Rodney
R
Srivastava
Jaya
J
Ivey
Kristopher
K
Ludaway
Tomika
T
Kapoor
Victor
V
Abuin
Allison
A
Shapoval
Alexsey
A
Santoianni
Robert
R
Saada
Ann
A
Elpeleg
Orly
O
Lewis
William
W
D000818:Animals; D044966:Anti-Retroviral Agents / Q000633:toxicity*; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000209:etiology; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000209:etiology; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D017354:Point Mutation; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014463:Ultrasonography
D044966:Anti-Retroviral Agents; D004272:DNA, Mitochondrial; D013385:Succinate Dehydrogenase; C105339:thymidine kinase 2; D013937:Thymidine Kinase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D042967:Electron Transport Complex I