2. Academic Validation
  3. Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system

Azidothymidine-triphosphate impairs mitochondrial dynamics by disrupting the quality control system

  • Redox Biol. 2017 Oct;13:407-417. doi: 10.1016/j.redox.2017.06.011.
Ryosuke Nomura 1,  Takeya Sato 2,  Yuka Sato 3,  Jeffrey A Medin 4,  Shigeki Kushimoto 5,  Teruyuki Yanagisawa 6
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ward, Sendai, Miyagi 980-8575, Japan; Department of Emergency and Critical Care, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ward, Sendai, Miyagi 980-8574, Japan. Electronic address: arumon-r@med.tohoku.ac.jp.
  • 2 Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ward, Sendai, Miyagi 980-8575, Japan. Electronic address: tksato@med.tohoku.ac.jp.
  • 3 Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ward, Sendai, Miyagi 980-8575, Japan. Electronic address: yuka_dazzle_1201@yahoo.co.jp.
  • 4 Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, CRI: C4540, Milwaukee, WI 53226, USA. Electronic address: jmedin@mcw.edu.
  • 5 Department of Emergency and Critical Care, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ward, Sendai, Miyagi 980-8574, Japan. Electronic address: kussie@emergency-medicine.med.tohoku.ac.jp.
  • 6 Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ward, Sendai, Miyagi 980-8575, Japan. Electronic address: yanagswt@med.tohoku.ac.jp.
PMID: 28683400 DOI: 10.1016/j.redox.2017.06.011
Abstract

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 100µM 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.

Keywords

Cardiomyopathy; Metabolites; Mitochondrial dynamics; Mitochondrial function; Oxidative phosphorylation; Oxidative stress.

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