NRTI therapy is associated with mitochondrial DNA depletion, increased mitochondrial biogenesis and subcutaneous fat wasting in HIV infected patients
Nolan, D., Hammond, E., Martin, A., Metcalf, C., Latham, B., John, M. and Mallal, S. (2001) NRTI therapy is associated with mitochondrial DNA depletion, increased mitochondrial biogenesis and subcutaneous fat wasting in HIV infected patients. In: 1st IAS Conference on HIV Pathogenesis and Treatment, 8 - 11 July 2001, Buenos Aires, Argentina
Background: Increased exposure to NRTIs in HIV infected patients predisposes to development of subcutaneous fat wasting (lipoatrophy). We sought to determine whether fat wasting was associated with mitochondrial DNA (mtDNA) depletion in subcutaneous fat. Methods:Subcutaneous fat from 11 HIV-infected patients on antiretroviral therapy, three HIV-infected, ART-naive patients and four HIV-negative healthy controls was examined by light and electron microscopy. The mtDNA and nuclear (n)DNA content was quantified by real time PCR-based assay and mitochondrial protein content (ng/mg tissue) was measured by biorad microplate assay.
Results: Light microscopy demonstrated adipose cell loss, increased variation in adipocyte size and lipogranulomata in patients with fat wasting compared with controls. Electron microscopy revealed markedly expanded adipocyte cytoplasm containing lipid droplets and abundant mitochondria with abnormal budding, elongated forms and abnormal whorled cristae. Deposition of granular material was noted on the inner aspect of adipocyte membranes. Untreated patients showed occasional lipogranulomata and intra-cytoplasmic lipid droplets only. MtDNA depletion was correlated with increased mitochondrial protein content (p=0.02). There was no significant difference between mtDNA/nDNA ratios from 4 controls (mean +/- SD, 57.2% +/- 10.5%) and 3 HIV-infected ART-naïve patients (45.2% +/- 19.5%) (P = 0.33). Compared with the combined control groups, patients receiving ZDV or d4T based ART (n=9) showed mtDNA depletion (20.0 +/- 9.8% vs 52.0 +/- 14.8%, P<0.0001). Within the ART group, patients with clinically apparent fat wasting had lower mtDNA/DNA ratios than those without (n=5), (14.0 +/- 4.2% vs 25.9 +/- 10.6%, p<0.05).
Conclusions: NRTI therapy is associated with mtDNA depletion, increased mitochondrial proliferation and fat wasting. NRTI-induced mtDNA depletion in fat may stimulate mitochondrial biogenesis as is seen in congenital mitochondrial diseases.
|Publication Type:||Conference Paper|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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