Species-specific mitochondria dynamics and metabolism regulate the timing of neuronal development

Abstract

The evolution of species involves changes in the timeline of key developmental programs. Among these, neuronal development is considerably prolonged in the human cerebral cortex compared with other mammals, leading to brain neoteny. Here we explore whether mitochondria influence the species-specific properties of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower pattern of mitochondria development in human cortical neurons compared with the mouse, together with lower mitochondria metabolic activity, particularly oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated maturation, leading to excitable and complex cells weeks ahead of time. Our data identify mitochondria as important regulators of the pace of neuronal development underlying human-specific features of brain evolution.

A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals

“…One potential mechanism underlying the differences in developmental tempo has been proposed to be metabolism. Recent studies done in mouse and human cells described the impact of metabolism on the segmentation clock or other developmental processes such as corticogenesis 28,30 . While it is clear that changes in metabolism can influence the developmental rate within a given species, the metabolic characterization done in this study indicates that intrinsic species-specific differences in the segmentation clock period or the speed of HES7 biochemical reactions are not directly derived from differential metabolic rates.…”

Generation of human cerebral organoids with a structured outer subventricular zone

“…Another interesting hypothesis is that the derivatives of oRG might mature faster than those derived from aRG and future studies will be needed to shed light on these possibilities. Interestingly, OXPHOS related genes showed increased expression in LIF-treated oRG, and forced enhancement of OXPHOS has been linked to accelerated neuronal maturation (Iwata et al, 2021).…”

Oxygen and the Spark of Human Brain Evolution: a Complex Systems Account

“…For example, metabolism and vascular health are already well-known factors underpinning psychiatric disorders (Baruah and Vasudevan, 2019, Meier et al, 2013, Sukumar et al, 2020, Turkheimer et al, 2020. By emphasising the role of metabolism in controlling growth and cellular composition during brain maturation (Iwata et al, 2021), this model points to a clear need for imaging technologies able to assay blood flow as well as oxygen and glucose metabolic rates in very young cohorts. Hence, experimental metabolic modulation should be added to current advanced organoid research (Notaras et al, 2021) both to illustrate how metabolic deficits may precipitate genetic risks for mental or degenerative disorders, or how enhanced metabolism may recover genetic phenotypes.…”

“…Conversely, proliferation and neurogenesis of hippocampal neural stem/progenitor cells of the mouse is impaired by a genetic mutation that compromises lipid metabolism, leading to cognitive deficits; furthermore, embryonically derived cerebral organoids also showed reduced proliferation, aerobic glycolysis correlates with cortical neoteny (Goyal et al, 2014). Importantly, new evidence points to metabolism, via mitochondrial maturation, as controlling the timing of brain development: oxidative phosphorylation is less prevalent and mitochondrial development slower in human cortical neurons, compared with mouse neurons (Iwata et al, 2021).…”