title: Permeability transition pore-mediated mitochondrial superoxide flashes regulate cortical neural progenitor differentiation.
abstract: In the process of neurogenesis, neural progenitor cells (NPCs) cease dividing and differentiate into postmitotic neurons that grow dendrites and an axon, become excitable, and establish synapses with other neurons. Mitochondrial biogenesis and aerobic metabolism provide energy substrates required to support the differentiation, growth and synaptic activity of neurons. Mitochondria may also serve signaling functions and, in this regard, it was recently reported that mitochondria can generate rapid bursts of superoxide (superoxide flashes), the frequency of which changes in response to environmental conditions and signals including oxygen levels and Ca(2+) fluxes. Here we show that the frequency of mitochondrial superoxide flashes increases as embryonic cerebral cortical neurons differentiate from NPCs, and provide evidence that the superoxide flashes serve a signaling function that is critical for the differentiation process. The superoxide flashes are mediated by mitochondrial permeability transition pore (mPTP) opening, and pharmacological inhibition of the mPTP suppresses neuronal differentiation. Moreover, superoxide flashes and neuronal differentiation are inhibited by scavenging of mitochondrial superoxide. Conversely, manipulations that increase superoxide flash frequency accelerate neuronal differentiation. Our findings reveal a regulatory role for mitochondrial superoxide flashes, mediated by mPTP opening, in neuronal differentiation.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hou
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Aiwu
authors.initials: A
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D015151:Immunoblotting; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055748:SOXB1 Transcription Factors; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014404:Tubulin; C462941:beta3 tubulin, mouse; D013481:Superoxides; D001278:Atractyloside; D016572:Cyclosporine; D045304:Cytochromes c; D013482:Superoxide Dismutase