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

Ryosuke Nomura, Takeya Sato, Yuka Sato, Jeffrey A. Medin, Shigeki Kushimoto, Teruyuki Yanagisawa

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)407-417
Number of pages11
JournalRedox Biology
Publication statusPublished - 2017 Oct


  • Cardiomyopathy
  • Metabolites
  • Mitochondrial dynamics
  • Mitochondrial function
  • Oxidative phosphorylation
  • Oxidative stress

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry


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