| Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS. | |
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MedLine Citation:
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PMID: 15951836 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2', 3'-didehydro-2', 3'-deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3' azido-3'-deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs. |
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Authors:
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William Lewis; Chad P Haase; Yoon K Miller; Brandy Ferguson; Tami Stuart; Tomika Ludaway; Jamie McNaught; Rodney Russ; Jeffrey Steltzer; Robert Santoianni; Robert Long; Giuseppe Fiermonte; Ferdinando Palmieri |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Laboratory investigation; a journal of technical methods and pathology Volume: 85 ISSN: 0023-6837 ISO Abbreviation: Lab. Invest. Publication Date: 2005 Aug |
Date Detail:
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Created Date: 2005-10-05 Completed Date: 2005-10-31 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376617 Medline TA: Lab Invest Country: United States |
Other Details:
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Languages: eng Pagination: 972-81 Citation Subset: IM |
Affiliation:
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Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. wlewis@emory.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acquired Immunodeficiency Syndrome
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drug therapy* Animals Antiretroviral Therapy, Highly Active / adverse effects Electrocardiography Lactic Acid / blood Membrane Transport Proteins / genetics, physiology* Mice Mice, Transgenic Microscopy, Electron, Transmission Mitochondria, Heart / drug effects*, ultrastructure Reverse Transcriptase Inhibitors / adverse effects* |
| Grant Support | |
ID/Acronym/Agency:
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HL059798/HL/NHLBI NIH HHS; R01 HL072707/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Membrane Transport Proteins; 0/Reverse Transcriptase Inhibitors; 0/SLC25A19 protein, human; 50-21-5/Lactic Acid |
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