Antiretroviral nucleoside and nucleotide analogues and mitochondria

This review is intended to provide understanding ofthe function of mitochondria, the advantages anddisadvantages of available techniques for assessing mitochondrialfunction and quantity and to discuss the mainclinical toxicities thought to be associated with mitochondrialdysfunction and how they may be managedor their prevalence reduced.Mitochondria are the key organelles in energy productionin all human cells except erythrocytes. Energy, inthe form of ATP, is produced through the highlyefficient oxidative phosphorylation pathway. Additionally,mitochondria perform a range of other biologicalfunctions and carry a number of factors involved in cellapoptosis. Both HIV infection and antiretroviral nucleosideanalogues (nucleoside reverse transcriptaseinhibitors; NRTI) are known to affect mitochondrialDNA content and other aspects of mitochondrial function.A number of important clinical events occurringin individuals with HIV infection and on antiretroviraltherapy have been linked to mitochondrial injury anddysfunction. In vitro studies have demonstrated thatNRTI may differ in their effects on mitochondria andmay affect mitochondria in different cell lines in differentways. This is likely to influence the clinicalsyndromes associated with toxicity to these agents.Dideoxy-NRTI have the greatest affinity for mitochondrialDNA polymerase-ª, the enzyme responsiblefor mitochondrial DNA replication, whereas othernucleoside analogues may influence mitochondrialfunction also through other mechanisms. These differencesmay be important in choosing techniquesto evaluate the impact of antiretroviral agents onmitochondria.