Novel role of mitochondrial fusion factor Mfn1 in neural differentiation of human iPS cells

抄録

Human induced pluripotent stem cells (iPSCs) are expected as potential sources that provide human neural cells for drug development. However, the mechanisms underlying the neural differentiation of iPSCs remain largely unknown.

To understand the molecular mechanisms of the neural differentiation, we examined the difference of mitochondrial morphology between iPSCs and neural progenitor cells (NPCs), which were induced by dual SMAD inhibition method from iPSCs. Mitochondria were morphologically immature and fragmented in iPSCs. During the neural differentiation, mitochondria were matured and fused together. Since these mitochondrial morphologies are considered to be related with quality control that maintains mitochondrial function, including energy generation, we next examined the effects of mitochondrial dynamics which are mediated by fusion proteins (Mfn, Opa1) and fission proteins (Fis1, Drp1) on neural differentiation. Mfn1 knockdown (Mfn1-KD) increased fragmented mitochondria, and reduced mitochondrial membrane potential and ATP content in iPSCs. In addition, Mfn1-KD inhibited the induction of neural differentiation markers, such as PAX6, FOXG1 and NCAM in iPSCs. Using microarray screening in Mfn1-KD cells, we identified a transcriptional factor which was involved in neural differentiation at the downstream of Mfn1.

These data suggest that Mfn1-mediated mitochondrial fusion is involved in the neural differentiation of iPSCs.