Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system. Redox Biol 2017 Oct;13:407-417
Date
07/07/2017Pubmed ID
28683400Pubmed Central ID
PMC5498287DOI
10.1016/j.redox.2017.06.011Scopus ID
2-s2.0-85021668617 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Highly active anti-retrovirus therapy (HAART) has been used to block the progression and symptoms of human immunodeficiency virus infection. Although it decreases morbidity and mortality, clinical use of HAART has also been linked to various adverse effects such as severe cardiomyopathy resulting from compromised mitochondrial functioning. However, the mechanistic basis for these effects remains unclear. Here, we demonstrate that a key component of HAART, 3๊-azido-3๊-deoxythymidine (AZT), particularly, its active metabolite AZT-triphosphate (AZT-TP), caused mitochondrial dysfunction, leading to induction of cell death in H9c2 cells derived from rat embryonic myoblasts, which serve as a model for cardiomyopathy. Specifically, treatment with 100ยตM AZT for 48h disrupted the mitochondrial tubular network via accumulation of AZT-TP. The mRNA expression of dynamin-related protein (Drp)1 and the Drp1 receptor mitochondrial fission factor (Mff) was upregulated whereas that of optic atrophy 1 (Opa1) was downregulated following AZT treatment. Increased mitochondrial translocation of Drp1, Mff upregulation, and decreased functional Opa1 expression induced by AZT impaired the balance of mitochondrial fission vs. fusion. These data demonstrate that AZT-TP causes cell death by altering mitochondrial dynamics.
Author List
Nomura R, Sato T, Sato Y, Medin JA, Kushimoto S, Yanagisawa TAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnti-HIV Agents
Cardiotoxicity
Cell Line
Dynamins
GTP Phosphohydrolases
Mitochondria
Mitochondrial Dynamics
Rats
Zidovudine
