Mitochondrial biogenesis and neural differentiation of human iPSC is modulated by idebenone in a developmental stage-dependent manner

J. Augustyniak, J. Lenart, M. Zychowicz, P. P. Stepien, L. Buzanska. Biogerontology (2017) 18: 665. doi:10.1007/s10522-017-9718-4

Idebenone, the synthetic analog of coenzyme Q10 can improve electron transport in mitochondria. Therefore, it is used in the treatment of Alzheimer’s disease and other cognitive impairments. However, the mechanism of its action on neurodevelopment is still to be elucidated. Here we demonstrate that the cellular response of human induced pluripotent stem cells (hiPSC) to idebenone depends on the stage of neural differentiation. When: neural stem cells (NSC), early neural progenitors (eNP) and advanced neural progenitors (NP) have been studied a significant stimulation of mitochondrial biogenesis was observed only at the eNP stage of development. This coexists with the enhancement of cell viability and increase in total cell number. In addition, we report novel idebenone properties in a possible regulation of neural stem cells fate decision: only eNP stage responded with up-regulation of both neuronal (MAP2), astrocytic (GFAP) markers, while at NSC and NP stages significant down-regulation of MAP2 expression was observed, promoting astrocyte differentiation. Thus, idebenone targets specific stages of hiPSC differentiation and may influence the neural stem cell fate decision.

Furthermore, the specific for eNP upregulation of all tested genes involved in the mitochondrial biogenesis as well as significant upregulation of viability may suggest that eNP stage is the “developmental window of sensitivity” for the neuroprotective function of the idebenone. More research is needed to elucidate the effect of idebenone on mitochondrial biogenesis and stem cell fate decision during neural differentiation, however, based on the presented results we can strongly support the hypothesis that idebenone protective effect is developmental stage dependent and that future targeted treatment of the selected stage of neural development may exert better therapeutic effect.