Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS.
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.
Lewis
William
W
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. wlewis@emory.edu
Haase
Chad P
CP
Miller
Yoon K
YK
Ferguson
Brandy
B
Stuart
Tami
T
Ludaway
Tomika
T
McNaught
Jamie
J
Russ
Rodney
R
Steltzer
Jeffrey
J
Santoianni
Robert
R
Long
Robert
R
Fiermonte
Giuseppe
G
Palmieri
Ferdinando
F
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D004562:Electrocardiography; D019344:Lactic Acid / Q000097:blood; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*
D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D018894:Reverse Transcriptase Inhibitors; C434255:SLC25A19 protein, human; D019344:Lactic Acid