Mechanisms of antiretroviral therapy-induced mitochondrial dysfunction

Purpose of review To discuss novel developments related to the mechanisms of antiretroviral therapy-related mitochondrial toxicity, describe some apparent paradoxes in the current understanding of this field, and present questions that should be addressed by future research. Recent findings The early polymerase g hypothesis states that nucleoside reverse transcriptase inhibitors can inhibit mitochondrial DNA replication and cause mitochondrial toxicity through mtDNA depletion. This mechanism is supported by a large body of evidence. Clinical manifestations of mitochondrial dysfunction are not always associated with mtDNA depletion. Increased mtDNA levels after nucleoside reverse transcriptase inhibitor exposure, as well as seemingly severe mtDNA depletion in individuals who show no clinical toxicity, have been reported. These and other observations suggest that additional mechanisms are involved in antiretroviral therapy toxicity, a notion supported by recent studies. Individuals given the same antiretroviral regimen can differ vastly with respect to the development of mitochondrial toxicity symptoms, reflecting interindividual variability. Some factors that may modulate this variability will be discussed. Summary Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors and their metabolic intermediates is probably mediated through many direct and indirect mechanisms. Depending on the mechanisms at play, the long-term health consequences of this toxicity may vary.