Linking mitochondria metabolism, developmental timing, and human brain evolution

Abstract

Changes in developmental timing are an important factor of evolution in organ shape and function. This is particularly striking for human brain development, which, compared with other mammals, is considerably prolonged at the level of the cerebral cortex, resulting in brain neoteny. Here, we review recent findings that indicate that mitochondria and metabolism contribute to species differences in the tempo of cortical neuron development. Mitochondria display species-specific developmental timeline and metabolic activity patterns that are highly correlated with the speed of neuron maturation. Enhancing mitochondrial activity in human cortical neurons results in their accelerated maturation, while its reduction leads to decreased maturation rates in mouse neurons. Together with other global and gene-specific mechanisms, mitochondria thus act as a cellular hourglass of neuronal developmental tempo and may thereby contribute to species-specific features of human brain ontogeny.

Figure 1

Potential mechanisms underlying species-specific developmental timing of cortical neurons. (a) PSC-derived cortical neurons from different species xenotransplanted into mouse neonatal cortex develop at their own species-specific rate, pointing to cell-intrinsic regulatory mechanisms of developmental timing. Plain line: neurons in their native brain environment; dashed line: neurons xenotransplanted in the mouse. (b) Schematic representation of mechanisms of species-specific developmental timing. (upper panel) GRN components controlling neuronal development are divergent, thus containing species-specific patterns of gene expression or species-specific genes. (lower panel) The GRN is largely conserved between species, but the speed at which they progress over time is driven by divergent global processes, including mitochondria metabolism, chromatin remodeling, and proteostasis. Note that the two mechanisms are nonmutually exclusive: both participate to human cortical neuron neoteny. See text for more details.

Figure 2

Linking mitochondria metabolism and the tempo of cortical neuron maturation. (a) Schematic of the NNN genetic labeling, which enables molecular and cellular analyses of neurons born at the same time. (b) Schematic of the relationships between mitochondria metabolism and neuronal developmental tempo across mouse and human species and following treatments leading to increased or decreased metabolism. Mouse cortical neurons display faster mitochondria development and higher metabolic rates than human counterparts. Increasing oxidative metabolism (oxphos) leads to increased mouse and human neuron maturation, while decreasing oxphos slows down mouse neuron maturation. Gray dashed line: experimental time of metabolomics analysis performed in mouse and human neurons at the same age. (c) Schematic of the metabolic patterns of mouse and human cortical neurons as measured at time point t represented in panel (b): higher aerobic glycolysis in human neurons and a higher mitochondrial metabolic activity in mouse neurons. (d) Schematic of the manipulation of metabolism of mouse or human cortical neurons and their impact on neuronal development. LDHA inhibition leads to increased pyruvate to lactate conversion, and AlbuMAX enrichment in fatty acid leads to increased acetyl-coA. Both treatments lead to increased mitochondrial metabolic activity, resulting in accelerated neuronal maturation rate. Inhibition of mitochondrial pyruvate carrier or of the complex I of the ETC results in decreased mitochondrial activity, which slows down mouse cortical neuron maturation.