Evidence of Mitochondrial Toxicity in Fat and Peripheral Blood Mononuclear Cells

Research has shown that certain antiretroviral drugs -- in particular, some nucleoside reverse transcriptase inhibitors (NRTIs) -- can cause mitochondrial toxicity, or damage to energy-producing structure within the cells. Mitochondrial toxicity may be responsible for lactic acidosis (elevated blood lactate), enlarged fatty liver, peripheral neuropathy, and other NRTI-associated side effects.

Levels of mitochondrial DNA (mtDNA) in body tissues have been proposed as a marker of NRTI toxicity, but clinical studies to date have yielded conflicting data regarding associations with mtDNA levels.

A study reported in the August 1, 2006 Journal of Acquired Immune Deficiency Syndromes analyzed mtDNA levels in matched samples of peripheral blood mononuclear cells (PBMCs) and subcutaneous fat tissue from a cohort of patients in Australia. The researchers examined treatment, clinical, and demographic factors associated with mtDNA depletion; mtDNA was quantified using real-time polymerase chain reaction assays.

Results

163 PBMC samples and 161 fat samples were obtained from 61 individuals.

Current NRTI exposure was the major determinant of mtDNA levels.

Both ddI (didanosine, Videx) and d4T (stavudine, Zerit) were associated with mtDNA depletion in fat tissue (P < 0.0001 vs patients not on NRTIs).

ddI exposure (P = 0.003) -- but not d4T exposure (P = 0.5) -- was associated with mtDNA depletion in PBMCs.

No association was observed between mtDNA levels and patient demographic factors or duration of time on current antiretroviral therapy.

Conclusion

"Current NRTI exposure is the major determinant of tissue mtDNA, but the precise determinants are tissue specific," the authors concluded. "Both ddI and d4T exposure are associated with fat mtDNA depletion, whereas ddI exposure was the only observed association with mtDNA depletion in PBMCs."

8/01/06

Reference
C L Cherry, D Nolan, I R James, and others. Tissue-Specific Associations Between Mitochondrial DNA Levels and Current Treatment Status in HIV-Infected Individuals. Journal of Acquired Immune Deficiency Syndromes 42(4): 435-440. August 1, 2006.