title: Mfn2 is Required for Mitochondrial Development and Synapse Formation in Human Induced Pluripotent Stem Cells/hiPSC Derived Cortical Neurons.
abstract: Mitochondria are essential dynamic organelles for energy production. Mitochondria dynamically change their shapes tightly coupled to fission and fusion. Imbalance of fission and fusion can cause deficits in mitochondrial respiration, morphology and motility. Mfn2 (mitofusin 2), a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, contributes to the maintenance and operation of the mitochondrial network. Due to lack of applicable model systems, the mechanisms and involvement of mitochondria in neurogenesis in human brain cells have not been well explored. Here, by employing the human induced pluripotent stem cells (hiPSCs) differentiation system, we fully characterized mitochondrial development, neurogenesis and synapse formation in hiPSCs-derived cortical neurons. Differentiation of hiPSCs to cortical neurons with extended period demonstrates mature neurophysiology characterization and functional synaptic network formation. Mitochondrial respiration, morphology and motility in the differentiated neurons also exhibit pronounced development during differentiation. Mfn2 knock-down results in deficits in mitochondrial metabolism and network, neurogenesis and synapse formation, while Mfn2 overexpression enhances mitochondrial bioenergetics and functions, and promotes the differentiation and maturation of neurons. Together, our data indicate that Mfn2 is essential for human mitochondrial development in neuronal maturation and differentiation, which will enhance our understanding of the role of Mfn2 in neurogenesis.
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA.
authors.forename: Du
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacology, University of Kansas, Lawrence, KS, USA.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D016708:Synaptophysin; C498585:TUBB3 protein, human; D014404:Tubulin; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human