Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8286867 | Redox Biology | 2017 | 61 Pages |
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, 3ê-azido-3ê-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.
Keywords
JC-1HRPnDNAguanosine triphosphate hydrolaseGAPDHTMPKHAARTAZT-TPMPTPDrp1GTPMFNAZTMFFPBSFACSCalcein-AMOCRDMEMAZT monophosphateGTPaseFBSNRTIIgGcDNAComplementary DNAMitochondrial DNANuclear DNADulbecco's modified Eagle Mediumopa1ROSoptic atrophy 1Adenosine TriphosphateATPmitochondrial permeability transition poreimmunoglobulin GOxidative stressThymidylate kinasefluorescence-activated cell sortingdihydroethidiumMitochondrial dynamicsmtDNAfetal bovine serumMitochondrial functionmitochondrial fission factorOxidative phosphorylationMetabolitesPhosphate-buffered salinenucleoside reverse transcriptase inhibitorMitofusinOxygen consumption ratewild typeDHEhuman immunodeficiency virusHIVHorseradish peroxidaseCardiomyopathyhigh-performance liquid chromatographyHPLCcalcein acetoxymethyl esterglyceraldehyde 3-phosphate dehydrogenaseGuanosine triphosphateReactive oxygen species
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Authors
Ryosuke Nomura, Takeya Sato, Yuka Sato, Jeffrey A. Medin, Shigeki Kushimoto, Teruyuki Yanagisawa,