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Nobiletin Exhibits Neuroprotective Effects against Mitochondrial Complex I Inhibition via Regulating Apoptotic Signaling

Experimental Neurobiology 2021년 30권 1호 p.73 ~ 86
Amarsanaa Khulan, 김혜지, 고은아, 조재민, 정성철,
소속 상세정보
 ( Amarsanaa Khulan ) - Jeju National University School of Medicine Department of Physiology
김혜지 ( Kim Hye-Ji ) - Jeju National University School of Medicine Department of Physiology
고은아 ( Ko Eun-A ) - Jeju National University School of Medicine Department of Physiology
조재민 ( Jo Jae-Min ) - Jeju National University School of Medicine Department of Internal Medicine
정성철 ( Jung Sung-Cherl ) - Jeju National University School of Medicine Department of Physiology

Abstract


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.

키워드

Nobiletin; Mitochondria; Electron transport chains; Complex I; ROS; Apoptosis-inducing factor

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