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

Biogerontology. 2017 Aug;18(4):665-677. doi: 10.1007/s10522-017-9718-4. Epub 2017 Jun 22.

Abstract

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.

Keywords: Astrocytic differentiation; Developmental neurotoxicity; Idebenone; Mitochondrial biogenesis; Neural progenitors; Neuronal; hiPSC; mtDNA copy number.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cell Line
  • Cell Lineage
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation
  • Humans
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neurogenesis / drug effects*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Organelle Biogenesis*
  • Phenotype
  • Reactive Oxygen Species / metabolism
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / pharmacology

Substances

  • Biomarkers
  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • Ubiquinone
  • idebenone