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

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 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.

Zidovudine-Mediated Autophagy Inhibition Enhances Mitochondrial Toxicity in Muscle Cells

“…Thus, it is conceivable to expect that the potential cumulative side effects of NRTIs may lead to long-term tissue damage in the population aging with HIV/AIDS (13)(14)(15). In that regard, long-term therapy with zidovudine has been associated with a toxic mitochondrial myopathy (16) and myocyte mitochondrial dysfunction with increased ROS production, confirmed by both in vitro and in vivo studies (2,3,10,11,17,18).…”

Toward a broader view of mechanisms of drug cardiotoxicity

“…133 Moreover, anti-HIV therapies have also been shown to inhibit the mitochondrial fusion-fission cycle. 8 Local anesthetics have been suggested to interact with phospholipids on the mitochondrial membrane, which often result in increased membrane permeability, electron transport chain disruption, and calcium accumulation. 134 Growth factors and cytokine signaling Growth factors and cytokines are biologically active molecules that act directly on many cellular functions, such as adhesion, proliferation, and migration.…”

“…However, recent studies have shown that a considerable number of drugs in use can also disrupt cardiac function by impairing myocardial metabolism and cardiac structure. These include anticancer therapies associated with myocardial apoptosis, 5 neurodegenerative disease agents with severe risk of fibrotic valvular heart disease, 6 or anti-bacterial 7 and antiviral 8 treatments leading to mitochondrial damage.…”

Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy

“…Mitochondrial fission is divided into the fission of membranes and outer membranes in mitochondria and is regulated by DRP1 ( 43 , 44 ). DRP1 is classified as a homologous protein of guanosine triphosphate (GTP) hydrolyzed enzyme (GTPase) power protein.…”

“…Mitochondrial fusion is divided into outer membrane fusion and endometrial fusion. It is regulated by a variety of proteins, including mitofusin (MFN) in the outer membrane of mitochondria and optic atrophy protein 1 (OPA1) ( 44 , 45 , 49 , 51 , 56 – 61 ). Among them, mitofusin 1 (MFN1) and mitofusin 2 (MFN2) regulate mitochondrial outer membrane fusion.…”