Drp1-Mediated Mitochondrial Fission Is Essential for Chemical-Induced Neuronal Transdifferentiation from Human Primary Fibroblasts.

Abstract

Neuronal replacement therapy recently holds promise for neurodegenerative disease treatment. Somatic cell-derived neurons are the main cell source for this therapy; however, the induction mechanisms remain to be fully elucidated. Emerging evidence indicates that mitochondrial architecture undergoes substantial remodeling throughout cellular reprogramming processes. To explore the implications of mitochondrial dynamics in chemical-induced neuronal transdifferentiation, human foreskin fibroblasts (HFFs) were directly reprogrammed into functional neurons with our previously developed small molecule compound. The results showed that the mitochondrial morphology of HFFs shifted from tubular and reticular to fragmented shapes at an early stage of induced neurulation. Concurrently, gene and protein expression levels of the mitochondrial fission protein Drp1 was significantly increased in HFFs after induction. Both Drp1-specific siRNA and Drp1-GTPase inhibitor mdivi-1 treatment significantly attenuated the neuronal transdifferentiation of HFFs to neurons respectively, which can be attributed to the modulation of mitochondrial dynamics toward a fusion-dominant state through Drp1 suppression. Collectively, our experimental findings establish Drp1-dependent mitochondrial fission as a critical early requirement in the chemical reprogramming cascade that facilitates HFF transdifferentiation into neuronal lineages. Targeting Drp1 may enhance the efficiency of neuronal transdifferentiation, thereby providing sufficient therapeutically relevant neurons for neurodegenerative disease treatment.