Neuronal Development Pace Is Dictated by Mitochondrial Metabolism Unique to Each Species

The temporal order of events that occur during embryonic development is often constant throughout evolution. However, it can happen at very varied time spans based on the species or cell kind taken into consideration. In comparison to other species, the human cerebral cortex exhibits significantly delayed neuronal maturation, taking months to years as opposed to just a couple of weeks in the mouse. Neoteny that results from this process is regarded as a crucial mechanism permitting improved brain function and plasticity. When cultivated in vitro or xenotransplanted into the mouse brain, human and nonhuman cortical neurons mature according to their respective species’ timeframes. This implies that species-specific developmental timing is regulated by cell-intrinsic mechanisms; however, these mechanisms are still mostly unknown.

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Mitochondria

Mitochondria

Cell fate is regulated by mitochondria

In many systems, such as the developing brain, cell fate transitions are primarily regulated by metabolism and mitochondria. A team of researchers has explored their potential roles in the species-specific rate of cortical neuron growth in the nascent human brain. The development of mouse and human cortical neurons was directly compared throughout time using a system of genetic birth-dating that was created to mark newly born neurons with great temporal and cellular resolution. Thus, the following were examined: mitochondrial architecture, genetic expression, oxygen utilization, and glucose metabolism across time and species. The rate of nerve cell development was then examined as a result of pharmacological or genetic treatment of human or mouse neurons to increase or decrease their mitochondrial activity.

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In newborn neurons, it was discovered that mitochondria start out small and are insufficient before gradually expanding as neurons mature according to a species-specific timeframe. Unlike mouse neurons, where mitochondria attain their mature patterns in 3–4 weeks, human neurons take several months to reach this stage. Next, an assessment was carried out on glucose metabolism and mitochondrial oxidative activity in cortical neurons in both mouse and human development. This revealed that mitochondrial functional maturation followed a species-specific timeframe, with mouse neurons increasing their mitochondria-dependent oxidative activity significantly more quickly than human neurons. Additionally, we discovered that, compared to mouse neurons of the same age, human cortical neurons showed lower rates of mitochondria-driven glucose metabolism. Finally, they investigated whether mitochondrial function influences the timing of neural growth. To improve mitochondrial oxidative metabolism, they genetically or pharmacologically altered human cortical neurons that were still forming. This enhanced neural maturation, and in weeks before time neurons showed more mature characteristics such as complex morphology, elevated electrical excitability, and functional synapse formation. The maturation of mouse nerve cells was accelerated by similar treatments, but the development of mouse neurons was slowed down by the inhibition of mitochondrial metabolism.

Clinical significance

The modeling of neurological illnesses using pluripotent stem cells may benefit from enhanced human nerve cell maturation through metabolic manipulation, which is still severely hampered by prolonged neuronal development. The effect of neuronal neoteny on these illnesses could be tested using tools to speed up or slow down neuronal growth.

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Conclusion

The research pinpoints a temporal pattern of mitochondrial and metabolic development that is specific to each species and regulates the rate of neural maturation. Mitochondria play a crucial role in controlling the rate of neuronal development that underlies the neoteny of the human brain.

References

Mitochondria metabolism sets the species-specific tempo of neuronal development

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