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

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Highly active anti-retroviral therapy (HAART) is crucial for managing HIV but linked to adverse effects like cardiomyopathy.
• The precise mechanisms behind HAART-induced mitochondrial dysfunction and cell death remain incompletely understood.

Purpose of the Study:

• To investigate the mechanistic basis of 3'-azido-3'-deoxythymidine (AZT)-induced mitochondrial dysfunction and cell death.
• To elucidate the role of AZT's active metabolite, AZT-triphosphate (AZT-TP), in cardiac myoblast cell death.

Main Methods:

• Treatment of H9c2 rat embryonic myoblast cells with AZT.
• Analysis of mitochondrial morphology, AZT-TP accumulation, and expression of key mitochondrial dynamics proteins (Drp1, Mff, Opa1).

Main Results:

• AZT treatment (100µM, 48h) led to AZT-TP accumulation and disrupted mitochondrial tubular networks.
• Upregulation of Drp1 and Mff mRNA expression, and downregulation of Opa1 mRNA.
• Increased Drp1 translocation to mitochondria, impaired mitochondrial fission/fusion balance, and subsequent cell death.

Conclusions:

• AZT-TP accumulation is a key driver of mitochondrial dysfunction and cell death in cardiomyocytes.
• AZT disrupts mitochondrial dynamics by altering the balance of fission and fusion proteins.
• These findings clarify a mechanism for HAART-associated cardiomyopathy.