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Understanding Mitochondrial Toxicity Induced In Cardiac Tissue By Long-term Exposure To Antiretroviral Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | 5778
ISSN: 2161-0495

Journal of Clinical Toxicology
Open Access

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Understanding mitochondrial toxicity induced in cardiac tissue by long-term exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs)

International Toxicology Summit & Expo

Yongmin Liu

Keynote: J Clinic Toxicol

DOI: 10.4172/2161-0495.S1.001

D espite the highly-effective clinical impact of NRTI use during human pregnancy, for prevention of HIV-1 mother-to-child transmission, therapeutic experience has revealed fetal consequences of chronic maternal use that particularly affect the heart and manifest as mitochondrial dysfunction. Studies in this laboratory, using Erythrocebus patas monkeys, have shown cardiac molecular and morphological mitochondrial toxicity, persistent to 3 years of age, in offspring exposed in utero to human-equivalent protocols containing NRTIs. To model this toxicity, comprehend underlying mechanisms and explore the possibility of introducing protective measures, we have performed studies using cultured rat cardiomyocytes exposed long-term to the NRTIs Zidovudine (AZT) and Didanosine (ddI). Mitochondrial integrity in these cells was examined by Seahorse XF24 Analyzer, an instrument that measures: oxygen consumption rate (OCR, indicating mitochondrial oxidative phosphorylation capacity); and, extracellular acidification rate (ECAR, reflecting glycolysis). Mitochondrial morphological integrity was examined by Electron Microscopy (EM). In cells exposed to no drug, 50 μM AZT, or 50 μM AZT plus 50 μM ddI for 39 passages, OCR was consistently impaired and ECAR was consistently increased, over most passages, compared to the unexposed controls, while cytotoxicity was minimal. Cells treated long-term showed mitochondrial morphological damage by EM, reduced expression of PGC-1α, the master regulator of mitochondrial function, and reduced expression of its downstream transcription factors NRF-1, and mtTFA. To examine the hypothesis that increased expression of PGC-1α would protect mitochondria against NRTI toxicity, we used a lentivirus vector to overexpress PGC-1α in H9c2 cells. When PGC-1α overexpressing H9c2 cells were exposed to the AZT/ddI combination for several passages, the overexpressing cells showed restoration of the AZT/ddI-induced OCR impairment. An additional strategy for mitochondrial protection is the use of Tempol, an antioxidant nitroxide and stable free radical known to increase levels of mitochondrial uncoupling protein 2 (UCP2). When Tempol was given simultaneously with AZT/ddI to H9c2 cells for several passages, there was protection of mitochondria from the OCR reduction caused by AZT/ddI alone, and mitochondrial morphology, evaluated by EM, was improved. Overall, these studies show that mitochondrial compromise, induced by long- term AZT/ddI exposure in H9c2 cardiomyocytes, can be attenuated by up-regulation of PGC-1α, and can be partially prevented through the simultaneous use of Tempol, a mild mitochondrial uncoupling agent. Tempol is currently being evaluated in the patas monkey model to investigate potential protective properties in the patas heart
Yongmin Liu completed his Ph.D/MD in Chinese Academy of Medical Sciences, and got postdoctoral training in University of Texas HSC at San Antonio and Baylor College of Medicine. Currently he is a Staff Scientist at National Cancer Institute, NIH, USA. His research is focused on cancer metabolism and anti-HIV drug-induced toxicity. He has published more than twenty scientific papers