Background <p>Mitochondrial biogenesis is an adaptive reaction that restores metabolic equilibrium following mitochondrial malfunction. Lutein has been studied for its ability to inhibit hepatotoxicity caused by sodium fluoride (NaF) or irradiation by inducing mitochondrial biogenesis through AMPK-PGC1α signaling.</p> Methods and results <p>Animals were randomized to six groups: Group I (vehicle) received sunflower oil; group II (Lutein) received Lutein (40&#xa0;mg/kg) for two weeks; group III (NaF) received sodium fluoride (48&#xa0;mg/kg) for two weeks; group IV (NaF + Lutein) received NaF and 1&#xa0;h later received Lutein; group V (IRR) was exposed to 7&#xa0;Gy single dose of gamma rays, and group VI (IRR + Lutein) was provided Lutein for two weeks together with a single irradiation dose. Hepatotoxicity was reported following NaF or irradiation exposure, as increased serum ALT, AST, MDA, and 3-nitrotyrosine levels were detected, paired with decrease in albumin, total protein, GSH and Nrf2 expression. Both NaF and irradiation caused a decline in the mitochondrial biogenesis pathway PGC1α/TFAM, as well as a significant decrease in AMPK, ATP, complex I, and complex II levels as compared to control. In contrast, lutein improved the levels of these biomarkers, implying that it helped lessen hepatotoxicity caused by irradiation or NaF, by enhancing mitochondrial biogenesis and conserving energy metabolism.</p> Conclusion <p>The findings suggests that lutein plays a preventive role against NaF or gamma-radiation by activating AMPK-PGC1α mitochondrial biogenesis.</p>