Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS
Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS
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DOI：
10.1038/labinvest.3700301
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发表时间：
2005-08-01
影响因子：
5
通讯作者：
Palmieri, F
中科院分区：
文献类型：
--
作者：
Lewis, W;Haase, CP;Palmieri, F
核苷类逆转录酶抑制剂（NRTI）是治疗艾滋病的抗逆转录病毒药物，具有有限的线粒体副作用。线粒体脱氧核苷酸载体（DNC）转运磷酸化核苷用于线粒体DNA复制，并且可以将磷酸化NRTI转运到线粒体中。在心脏中专门过表达DNC的转基因小鼠（TG）测试了DNC在NRTIs线粒体功能障碍中的作用。创建了两个TG系，其在鼠心肌中过表达人DNC基因。通过磁共振成像、超声心动图、心电图、透射电子显微镜和血浆乳酸检查心脏和线粒体结构和功能。给予含有NRTI（司他夫定（2 '，3'-二氮基-2 '，3'-脱氧胸苷或d4 T）/拉米夫定/茚地那韦;或齐多夫定（3'叠氮基-3'-脱氧胸苷或AZT）/拉米夫定/茚地那韦; 35天）的抗逆转录病毒组合（HAART）以模拟AIDS治疗。同时，不含NRTI的HAART联合治疗（奈韦拉平/依法韦仑/茚地那韦; 35天）作为NRTI保留对照方案。未经处理的DNC TG表现出正常的心脏功能，但异常的线粒体超微结构。含有NRTI的HAART导致TG中的心肌病，左心室质量和体积增加，心率变异性增加，线粒体超微结构缺陷更严重。相反，NRTI保留HAART方案治疗未引起心脏变化。数据表明，DNC是体内线粒体稳态不可或缺的，可能与接受含NRTI的HAART方案治疗的患者的线粒体功能障碍有关。
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.