Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase...

Area of Science:

• Cellular Biology
• HIV Pathogenesis
• Mitochondrial Medicine

Background:

• Nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy is linked to subcutaneous fat wasting in HIV-infected individuals.
• Mitochondrial DNA (mtDNA) depletion is a proposed mechanism for NRTI-induced host toxicity.

Purpose of the Study:

• To investigate cellular mitochondrial DNA (mtDNA) copy number and mitochondrial mass in adipocytes from NRTI-treated HIV patients.
• To compare these parameters with antiretroviral-naive HIV-infected controls and HIV-seronegative controls.
• To assess adipose tissue morphology in relation to NRTI treatment.

Main Methods:

• Subcutaneous fat samples were collected from three groups: NRTI-treated HIV patients (n=21), antiretroviral therapy-naive HIV patients (n=11), and HIV-seronegative controls (n=6).
• Adipocyte mitochondrial DNA (mtDNA) copy number per cell was quantified using real-time PCR.
• Adipocyte mitochondrial protein content was measured, and tissue morphology was examined via light and electron microscopy.

Main Results:

• NRTI treatment significantly reduced adipocyte mtDNA copy number per cell by a mean of 77.7% compared to HIV-infected controls (P < 0.001).
• Stavudine treatment resulted in greater mtDNA depletion (87.1%) than zidovudine (52.1%) (P < 0.001).
• Adipocyte mitochondrial mass increased significantly (289%) in the stavudine group only (P < 0.01).

Conclusions:

• NRTI therapy is associated with significant mitochondrial DNA depletion in adipocytes.
• Mitochondrial proliferation in adipocytes, particularly with stavudine, suggests a compensatory or pathological response.
• Findings support the hypothesis that NRTI-induced mtDNA depletion contributes to subcutaneous fat wasting and adipocyte dysfunction.