Defective Mitochondrial and Peroxisomal Fission Dynamics Impair Neurogenesis

Abstract

Mitochondrial and peroxisomal dynamics driven by DRP1 are integral to many cellular functions. Mutations in DRP1 lead to a devastating neurodevelopmental disease known as encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1), which presents with a spectrum of symptoms including developmental delay, seizures, and microcephaly. To interrogate the molecular mechanisms by which DRP1 mutations lead to developmental defects, we used induced pluripotent stem cell (iPSC)-derived models with patient mutations in different domains of DRP1. Given that EMPF1 patients present with a spectrum of neurodevelopmental abnormalities, we differentiated iPSCs into neural progenitor cells and neural organoids. DRP1 mutant neural progenitor cells express lower levels of critical identity transcription factors, such as PAX6 and TBR2. Intriguingly, neural organoids with mutations in the stalk domain of DRP1 take on a choroid plexus identity instead of following a cortical development trajectory. Our results show that EMPF1 associated DRP1 mutations lead to metabolic dysregulation, which may cause changes in neural cell fate during early corticogenesis. Understanding these mechanisms will give insight into the role of mitochondrial and peroxisome dynamics in neurodevelopment, as well as the mechanisms underlying the rare disease EMPF1.