TY - JOUR
T1 - Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system
AU - Nomura, Ryosuke
AU - Sato, Takeya
AU - Sato, Yuka
AU - Medin, Jeffrey A.
AU - Kushimoto, Shigeki
AU - Yanagisawa, Teruyuki
N1 - Funding Information:
This work was supported by a Grant-in-aid for Scientific Research (C) by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number 24590311 to R.N.); JSPS KAKENHI (grant number 23618003 to T.S.); and by a Health and Labour Sciences Research Grant for research on/AIDS from the Ministry of Health Labour and Welfare (grant number 08004664 to T.S.).
Publisher Copyright:
© 2017 The Authors
PY - 2017/10
Y1 - 2017/10
N2 - 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, 3ꞌ-azido-3ꞌ-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 100 µM AZT for 48 h 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.
AB - 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, 3ꞌ-azido-3ꞌ-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 100 µM AZT for 48 h 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.
KW - Cardiomyopathy
KW - Metabolites
KW - Mitochondrial dynamics
KW - Mitochondrial function
KW - Oxidative phosphorylation
KW - Oxidative stress
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U2 - 10.1016/j.redox.2017.06.011
DO - 10.1016/j.redox.2017.06.011
M3 - Article
C2 - 28683400
AN - SCOPUS:85021668617
VL - 13
SP - 407
EP - 417
JO - Redox Biology
JF - Redox Biology
SN - 2213-2317
ER -