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 Ca2+ 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.
Highlights
Mitochondria function as ‘cellular power plants’, generating adenosine triphosphate (ATP) that is required for cell survival and function
Our findings reveal that during the process of differentiation of neural progenitor cells (NPCs) into neurons, mitochondrial permeability transition pore (mPTP)-mediated mitochondrial superoxide flash generation increases
By exposing NPCs to agents that either inhibit or enhance mitochondrial superoxide flash generation, we provide evidence mPTP opening and superoxide flash generation promotes the neuronal differentiation process
Summary
Mitochondria function as ‘cellular power plants’, generating adenosine triphosphate (ATP) that is required for cell survival and function. Mitochondria have many other functions in addition to the production of ATP, including roles in signal transduction and the regulation of cellular calcium homeostasis [1]. During the process of differentiation of neurons from neural progenitor cells (NPCs) mitochondrial biogenesis occurs to supply mitochondria for the growing dendrites and axon [5,6]. Because neurons are excitable cells and experience repeated bouts of membrane depolarization and Na+ and Ca2+ influx, they have a much higher aerobic metabolic rate than NPCs [7]. Because mitochondrial respiration generates superoxide anion radical, cells with greater amounts of active mitochondria, such as neurons and myocytes, produce more superoxide than non-excitable cells [1,8]
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