The
coffee diterpene kahweol (KW; C20H26O3) is a cytoprotective agent exhibiting potent
antioxidant actions, as demonstrated in several experimental models. In spite of the efforts to elucidate exactly how KW promotes cytoprotection, it was not previously examined whether KW would be able to protect mitochondria of human cells undergoing redox stress. In the present work, we have treated the human
neuroblastoma SH-SY5Y cell line with KW at 0.1-10 μM for 12 h prior to a challenge with
methylglyoxal (MG), a reactive dicarbonyl that impairs mitochondrial function. We have found that KW at 10 μM suppressed the loss of mitochondrial membrane potential (
MMP) and the bioenergetics decline (including decreased activity of the mitochondrial complexes I and V and reduced production of
adenosine triphosphate,
ATP) in the MG-treated SH-SY5Y cells. KW also prevented the MG-elicited generation of reactive
oxygen and
nitrogen species (ROS and RNS, respectively) in the SH-SY5Y cells. In this regard, KW exerted an
antioxidant effect on the membranes of mitochondria obtained from the MG-treated cells. The mitochondria-related effects induced by KW were blocked by inhibition of the
phosphoinositide 3-kinase (PI3K)/Akt or of the
p38 mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, silencing of the
transcription factor nuclear factor E2-related factor 2 (Nrf2) suppressed the mitochondrial protection promoted by KW in the MG-challenged cells. Therefore, KW protected mitochondria by a mechanism associated with the PI3K/Akt and
p38 MAPK/Nrf2 signaling pathways.