Cardiac-Targeted Transgenic Mutant Mitochondrial Enzymes

• Authors: James J Kohler, Emory University; Seyed H. Hosseini, Emory University; Elgin Green, Emory University; Amy Hoying-Brandt, Emory University; Ioan Cucoranu, Emory University; Chad P. Haase, Emory University; Rodney Russ, Emory University; Jaya Srivastava, Emory University; Kristopher Ivey, Emory University; Tomika Ludaway, Emory University; Victor Kapoor, Emory University; Allison Abuin, Emory University; Alexsey Shapoval, Emory University; Robert Santoianni, Emory University; Ann Saada, Hadassah University; Orly Elpeleg, Hadassah University; William Lewis, Emory University
• Journal Title: Cardiovascular Toxicology
• Volume: Volume 8, Number 2
• Publisher: Humana Press | 2008-04-30, Pages 57-69
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s12012-008-9015-1
• Subjects: Health Sciences, Toxicology
• Keywords: Cardiomyopathy; Murine model; mtDNA; NRTI; Toxicity

Abstract

Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (pol γ) 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 γ and mtDNA replication. Cardiac “dominant negative” murine transgenes (TGs; Pol γ Y955G, 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 × 2” studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs (∼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 (≈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.