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. •Mitochondria are essential for the development of hiPSC-derived DA neurons•Mitochondrial defects suppress maturation and synaptogenesis of DA neurons•ROS levels positively correlate to DA neuron maturation and synaptic formation•A model of crosstalk of mitochondrial network to neurogenesis of DA neurons In this article, Yan and colleagues comprehensively evaluate the properties of mitochondrial and synaptic structure and function during the development of hiPSC-derived dopaminergic (DA) neurons. Their data demonstrate that mitochondria are important in DA neuron maturation and synaptic formation. The model provides a link of mitochondrial alterations to synaptic failure and neurogenesis in the pathogenesis of neurodegenerative diseases including Parkinson’s disease.