Tissue-Specific Associations Between Mitochondrial DNA Levels and Current Treatment Status in HIV-Infected Individuals

Abstract

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

Impact of Nucleoside Reverse Transcriptase Inhibitors on Mitochondria in Human Immunodeficiency Virus Type 1-Infected Children Receiving Highly Active Antiretroviral Therapy

“…In a recent study with adults, d4T and ddI use was associated with fat mtDNA depletion, whereas ddI exposure was the only observed association with mtDNA depletion in PBMCs (10).…”

Mitochondrial Oxidative Phosphorylation Protein Levels in Peripheral Blood Mononuclear Cells Correlate with Levels in Subcutaneous Adipose Tissue within Samples Differing by HIV and Lipoatrophy Status

“…However, most published studies, as well as the results in this current study, indicate that mtDNA levels in PBMCs perform poorly in identifying mitochondrial toxicity in fat. 13,[15][16][17][18][39][40][41] This may be due in part to the difficulty in purifying PBMCs consistently without platelet contamination. Platelets have mitochondria (and mtDNA) but lack nuclei and variable platelet contamination may result in erratic mtDNA:nDNA ratio measurements.…”

“…Unfortunately, while mtDNA levels have been consistently demonstrated to be depleted in adipose tissue of lipoatrophic subjects, 7,[12][13][14] mtDNA levels in peripheral blood mononuclear cells (PBMCs) do not correlate well with either clinical lipoatrophy or with mtDNA levels in fat. 13,[15][16][17][18] Mitochondrial protein levels, and in particular levels of enzyme complexes of the oxidative phosphorylation system (OXPHOS), may be more informative indicators of mitochondrial function than are measurements of mtDNA. The mitochondrial OXPHOS system is essential for energy metabolism and normally provides more than 95% of ATP used for cellular energy.…”

Decrease of mitochondrial DNA level in sperm from patients infected with human immunodeficiency virus-1 linked to nucleoside analogue reverse transcriptase inhibitors

“…Decreased mitochondrial DNA (mtDNA) content has been described in adipose tissue from patients receiving NRTI treatment (15)(16)(17) and in vitro studies have demonstrated specific NRTI toxicity (18). In addition, in vivo tissue-selective toxicity has been reported (19,20) and polymerase gamma polymorphism may modify toxicity (13).…”

“…Changes in mtDNA in peripheral blood cells can precede blood lactate increase (31) and d4T and ddI molecules, in particular, showed a stronger association with blood lactate increase (32). However, tissue-selective toxicity yielded contradictory results between blood and specific tissues more susceptible to damage, such as muscle or adipose tissues (19). Spermatozoa are clinical materials that are easily obtained without invasive procedures and could be useful biological markers of the adverse effects of HAART (33), due to sperm mitochondrial sensitivity (23,24).…”