Tempol protects cardiomyocytes from nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity

Area of Science:

• Biochemistry
• Cardiology
• Pharmacology

Background:

• Nucleoside reverse transcriptase inhibitors (NRTIs) are crucial in human immunodeficiency virus-1 (HIV-1) treatment.
• NRTIs can induce mitochondrial damage in cardiac cells.

Purpose of the Study:

• To investigate the protective effects of antioxidants Tempol and Tempol-H against NRTI-induced mitochondrial damage in H9c2 rat cardiomyocytes.
• To elucidate the mechanisms underlying this protection, including effects on oxidative phosphorylation and superoxide levels.

Main Methods:

• H9c2 cells were exposed to zidovudine (AZT) and didanosine (ddI) for 16 passages, with or without Tempol or Tempol-H.
• Mitochondrial oxidative phosphorylation capacity was assessed using a Seahorse XF24 Analyzer.
• Electron microscopy (EM) and Western blotting were employed to evaluate mitochondrial pathology and protein expression (UCP-2, Complex I).
• Superoxide levels were measured to assess oxidative stress.

Main Results:

• NRTI exposure (AZT/ddI) led to moderate growth inhibition and significant reduction in mitochondrial oxidative phosphorylation capacity (8.8-57.2%).
• Co-administration of Tempol or Tempol-H with NRTIs increased oxidative phosphorylation by approximately 300% compared to NRTIs alone.
• EM studies showed reduced mitochondrial pathology in cells treated with NRTIs and Tempol.
• Tempol/Tempol-H upregulated mitochondrial uncoupling protein-2 (UCP-2) expression, but did not restore Complex I activity.
• Superoxide levels increased with NRTI exposure but decreased significantly with Tempol treatment.

Conclusions:

• Tempol and Tempol-H effectively protect against NRTI-induced mitochondrial compromise in cardiomyocytes.
• UCP-2 appears to play a role in this protection through mild uncoupling.
• Antioxidant intervention may mitigate cardiac side effects associated with NRTI therapy.