DNA polymerase-γ hypothesis in nucleoside reverse transcriptase-induced mitochondrial toxicity revisited: A potentially protective role for citrus fruit-derived naringenin?

Nucleoside reverse transcriptase inhibitors (NRTIs) form the backbone in combination antiretroviral therapy (cARVs). They halt chain elongation of the viral cDNA by acting as false substrates in counterfeit incorporation mechanism to viral RNA-dependent DNA polymerase. In the process genomic DNA polymerase as well as mitochondrial DNA (mtDNA) polymerase-γ (which has a much higher affinity for these drugs at therapeutic doses) are also impaired. This leads to mitochondrial toxicity that manifests clinically as mitochondrial myopathy, peripheral neuropathy, hyperlactatemia or lactic acidosis and lipoatrophy. This has led to the revision of clinical guidelines by World Health Organization to remove stavudine from first-line listing in the treatment of HIV infections. Recent reports have implicated oxidative stress besides mtDNA polymerase-γ hypothesis in NRTI-induced metabolic complications. Reduced plasma antioxidant concentrations have been reported in HIV positive patients on cARVs but clinical intervention with antioxidant supplements have not been successful either due to low efficacy or poor experimental designs. Citrus fruit-derived naringenin has previously been demonstrated to possess antioxidant and free radical scavenging properties which could prevent mitochondrial toxicity associated with these drugs. This review revisits the controversy surrounding mtDNA polymerase-γ hypothesis and evaluates the potential benefits of naringenin as a potent anti-oxidant and free radical scavenger which as a nutritional supplement or therapeutic adjunct could mitigate the development of mitochondrial toxicity associated with these drugs.