Development and Dynamic Regulation of Mitochondrial Network in Human Midbrain Dopaminergic Neurons Differentiated from iPSCs.
Mitochondria are critical to neurogenesis, but the mechanisms of mitochondria in neurogenesis have not been well explored. We fully characterized mitochondrial alterations and function in relation to the development of human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons. Following directed differentiation of hiPSCs to DA neurons, mitochondria in these neurons exhibit pronounced changes during differentiation, including mature neurophysiology characterization and functional synaptic network formation. Inhibition of mitochondrial respiratory chains via application of complex IV inhibitor KCN (potassium cyanide) or complex I inhibitor rotenone restricted neurogenesis of DA neurons. These results demonstrated the direct importance of mitochondrial development and bioenergetics in DA neuronal differentiation. Our study also provides a neurophysiologic model of mitochondrial involvement in neurogenesis, which will enhance our understanding of the role of mitochondrial dysfunctions in neurodegenerative diseases.
Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA.
Du
D
Fang
Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du 610041, China.
Yu
Y
Qing
Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA.
Shijun
S
Yan
Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA.
Doris
D
Chen
Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA. Electronic address: shidu@ku.edu.
Shirley ShiDu
SS
Yan
D015415:Biomarkers; D002454:Cell Differentiation; D002465:Cell Movement; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010641:Phenotype; D013569:Synapses / Q000378:metabolism
D015415:Biomarkers
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