Exp Neurobiol 2021; 30(1): 73-86
Published online January 11, 2021
© The Korean Society for Brain and Neural Sciences
Khulan Amarsanaa1, Hye-Ji Kim1, Eun-A Ko1, Jaemin Jo2 and Sung-Cherl Jung1,3,4*
1Department of Physiology, School of Medicine, Jeju National University, 2Department of Internal Medicine, School of Medicine, Jeju National University, 3Institute of Medical Science, Jeju National University, 4Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Korea
Correspondence to: *To whom correspondence should be addressed.
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Nobiletin, a polymethoxylated flavonoid found in citrus, has been studied because of its modulatory functions in cellular signaling cascades, and effects to prevent mitochondrial calcium overload and neuronal cell death. Particularly, we previously reported that nobiletin induced changes in the mitochondrial membrane potential through K+ channel regulation, suggesting that nobiletin might exert neuroprotective effects via regulating mitochondrial functions associated with the electron transport chain (ETC) system. This study investigated whether nobiletin regulated mitochondrial dysfunction mediated by ETC system downregulation by inhibiting complex I (CI) and complex III (CIII) in pure mitochondria and the cortical neurons of rats. The results showed that nobiletin significantly reduced mitochondrial reactive oxygen species (ROS) production, inhibited apoptotic signaling, enhanced ATP production and then restored neuronal viability under conditions of CI inhibition, but not CIII inhibition. These effects were attributed to the downregulation of translocation of apoptosis-induced factor (AIF), and the upregulation of CI activity and the expression of antioxidant enzymes such as Nrf2 and HO-1. Together with our previous study, these results indicate that the neuroprotective effects of nobiletin under mitochondrial dysfunction may be associated with its function to activate antioxidant signaling cascades. Our findings suggest the possibility that nobiletin has therapeutic potential in treating oxidative neurological and neurodegenerative diseases mediated by mitochondrial dysfunction.