Luteolin, a common flavone in vegetables, acts as a hormetin possessing neurotrophic function: signaling mediated by inducing mitochondrial stress

This study aims to uncover the hormetic process of luteolin, a common dietary flavone, in neuronal cells through its role in inducing mitochondrial stress. In rat pheochromocytoma PC12 cells, luteolin at low concentrations caused a mild and reversible loss of mitochondrial membrane potential (MMP), while high concentrations of luteolin triggered intense and sustained depolarization of MMP. The MMP disturbance was shown to have a close association with the trophic and/or toxic effects triggered by luteolin; because the common mitochondrial uncouplers shared similar bi-phase dose-response on cell viability, as that of luteolin. Along with the induced MMP pertubation, luteolin triggered the development of autophagy and mitophagy, as determined by mCherry-GFP-LC3B tandem protein, and by the co-localization of mitochondrial/lysosomal staining. Subsequent application of autophagy inhibitors in the cultures blocked the luteolin-induced neurotrophic activities and sensitized the cells to be less resistant to luteolin-mediated cytotoxicity. Other flavonoids also displayed similar properties in the cultures, indicating that these compounds act as hormetic pharmacological inducers that stimulate cells to become more resilient and adapt to threats. This study provides a unifying mechanistic explanation for the neuro-beneficial effects of luteolin and other flavonoids.