Adipocytes (fat cells) from patients using nucleoside analogue reverse transcriptase inhibitors (NRTIs) show evidence of mitochondrial toxicity after just a few months of therapy, according to a research letter published in the March 26th edition of AIDS. This study is the first to demonstrate in vivo that NRTI-associated depletion of mitochondrial DNA (mtDNA) in adipocytes has a negative effect on the function of mitochondrial respiratory proteins.
In contrast to the normal DNA that resides within the cell nucleus, mtDNA are short loops of genetic material, usually inherited only from the mother, that are present in a cell’s mitochondria, organelles involved in energy production.
Certain NRTIs such as d4T (stavudine) have been associated with fat loss (lipoatrophy). Researchers have hypothesized that NRTIs contribute to fat wasting by directly inhibiting the activity of mitochondrial-specific DNA polymerase gamma, an enzyme required for replication and repair of mtDNA, thus leading to mtDNA depletion in adipocytes and eventual cell death. This mechanism, the authors note, is analogous to how NRTIs block HIV replication by inhibiting viral RNA-directed DNA polymerase (reverse transcriptase).
Mitochondria produce energy by means of an elaborate respiratory chain in which glucose is broken down, electrons are transferred from molecule to molecule, and a compound called adenosine triphosphate (ATP) is produced. In this study, researchers assessed the activity of various proteins complexes that contribute to this process, including complex I (NADH), complex II (succinate dehydrogenase, or SDH) and complex IV (cytochrome C oxidase, or COX).
Mitochondrial enzyme activity was assessed in adipocytes from seven patients receiving antiretroviral regimens containing NRTIs. Within 6-12 months of starting therapy, researchers detected reduced mtDNA levels and decreased COX activity in six of the seven subjects. COX subunit I is encoded by mtDNA, and researchers detected reduced expression of this subunit in three of the seven subjects. Activity of SDH, which is encoded by nuclear rather than mitochondrial DNA, was not decreased. Although NADH, like COX, is also partially encoded by mtDNA, the researchers did not detect a reduction in NADH activity corresponding to mtDNA depletion.
Importantly, mitochondrial toxicity at the cellular level was seen early in the course of NRTI therapy, before any obvious changes in body composition were apparent.
The authors noted that various factors influence how specific NRTIs affect particular tissues, including the metabolic activity and energy requirements of different types of cells and how they process drugs into their active form. Therefore, the effects of NRTIs on fat cells cannot necessarily be assumed to be the same in other types of tissue such as the liver or muscles.
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Lipodystrophy booklet in the information for HIV-positive people series - pdf
Hammond E et al. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 18: 815–827, 2004.