Mitochondria Set the Tempo for Neuronal Development
Post by Elisa Guma
The takeaway
The development of neurons and mitochondria in the cerebral cortex takes considerably longer in the human brain than in other species, such as mice. Accelerating mitochondrial metabolism seems to accelerate human neuronal maturation, indicating that they are important regulators of the pace at which the brain develops.
What's the science?
There are striking species differences in the amount of time required for brains to develop, wherein the human brain develops over the course of months to years, while the mouse brain develops over the course of weeks. It is unclear what is responsible for these differences, however, given the important role that mitochondria play in driving cell maturation, they may also play a key role in modulating the differences in developmental timelines of cortical neurons. This week in Science, Iwata and colleagues investigate the role that mitochondria have in determining the developmental timelines of cortical neurons across the human and mouse brain.
How did they do it?
To investigate the relationship between mitochondrial metabolism and neuronal maturation, the authors used cultures of human and mouse cortical pyramidal neurons derived from pluripotent stem cells, as well as embryonic mouse brain neurons. For the pluripotent stem cells, the authors devised a method that stages neurons based on their birthdate to allow them to compare neurons in the same stage of development. To birthdate the neurons, the authors tagged the NeuronalDifferentiation1 gene – a gene that is active when the neuron enters a specific maturational stage – with a green fluorescent protein, allowing them to identify and separate it from the other neurons.
Within neurons of the same maturational stage, the authors also tagged mitochondria with an emerald-green fluorescent protein allowing them to visualize the morphology and location of these organelles within the neuron. To monitor mitochondria in developing cortical neurons in the mouse brain, the authors labeled mouse cortical neurons with a fluorescent protein using in utero electroporation in mid-late gestation, or they transplanted fluorescently labeled human neurons in the mouse brain. This allowed them to use light and electron microscopy to examine patterns of mitochondrial development and identify the age at which they reached maximal levels of growth and size.
Following a characterization of mitochondrial development, the authors examined the metabolic activity of mitochondria in both mouse and human cortical neurons at similar times after birth, focusing on mitochondrial oxidative phosphorylation and electron transport chain capacity (two indicators of metabolic function). Finally, to test whether enhanced mitochondrial activity would also accelerate neuronal development, the authors accelerated mitochondrial metabolism by inhibiting specific enzymes that are important in glucose metabolism in human cortical neurons.
What did they find?
In mouse pluripotent stem cells and newly born neurons (from the embryonic brain), the authors found that mitochondria were initially small and sparse but grew in quantity over the 3-week maturational window of these neurons. In contrast, pluripotent stem cells derived from human cortical neurons, as well as their mitochondria, showed a much slower pattern of maturation, taking several months. These data suggest that mitochondrial morphology and development follow a species-specific timeline that is highly correlated with neuronal maturation.
Consistent with morphological development, mitochondrial metabolism was higher in the mouse neurons than in the human neurons in the early stages of development and continued to increase at a faster rate across development. In human cortical neurons, they also observed lower levels of oxidative stress compared to the mouse neurons, consistent with lower activity of mitochondrial metabolism.
When the authors increased mitochondrial activity in human neurons, they observed an increase in oxidative phosphorylation with no significant alterations to mitochondrial morphology. However, they did observe an increase in the speed at which neurons were maturing both in terms of function (based on synaptic currents and membrane potentials) as well as morphology (larger neuronal size and increased dendritic length and complexity). This indicates the crucial role of these organelles in regulating timelines of neuronal development.
What's the impact?
This study provides evidence for the role of mitochondrial metabolic activity in regulating the species-specific developmental timeline of cortical neurons. When mitochondrial metabolism was enhanced, neurons showed accelerated morphological and functional maturation. This may in part explain why the human brain develops across much longer time courses than other species, such as the mouse. Future work is needed to understand the downstream effects of mitochondrial metabolism on brain function, plasticity, and neurodevelopmental disorders.
