Energy metabolism in childhood neurodevelopmental disorders

Abstract

Whereas energy function in the aging brain and their related neurodegenerative diseases has been explored in some detail, there is limited knowledge about molecular mechanisms and brain networks of energy metabolism during infancy and childhood. In this review we describe current insights on physiological brain energetics at prenatal and neonatal stages, and in childhood. We then describe the main groups of inborn errors of energy metabolism affecting the brain. Of note, scarce basic neuroscience research in this field limits the opportunity for these disorders to provide paradigms of energy utilization during neurodevelopment. Finally, we report energy metabolism disturbances in well-known non-metabolic neurodevelopmental disorders. As energy metabolism is a fundamental biological function, brain energy utilization is likely altered in most neuropediatric diseases. Precise knowledge on mechanisms of brain energy disturbance will open the possibility of metabolic modulation therapies regardless of disease etiology.

Keywords: Autism; Brain energy metabolism; Inborn errors of energy metabolism; Neurodevelopment; Rett syndrome.

Fig. 1

Energy metabolism during neurodevelopment: key molecules and their dynamics. Glucose, lactate and ketone bodies (KBs) are key players in energy metabolism during neurodevelopment. (a) Basic pathways for energy production. In a 7-days postnatal rat, glucose supports around 60% of brain energy demands, and KBs support 30% (24). (b) Substrate utilization dynamics in the brain throughout development.

Fig. 2

Perinatal to early infancy versus childhood to adolescence brain metabolism. Only main variations between both development times are shown. (a) In the neonatal brain, lactate and ketone bodies (KBs) uptake versus glucose ratio is higher than in the adult brain. Upon importation of glucose into the neuron, it will be preferentially metabolized through the pentose phosphate pathway, generating both NADPH and precursors for the synthesis of nucleotides, as well as key element in the antioxidant defense of the cell. Glucose might also be further metabolized for the generation of oxalacetate, a-Ketoglutarate and pyruvate, all precursors of amino acids which also have specific roles as neurotransmitters (NTs), as is the synthesis of glutamate. Lactate and KBs are taken up by the cell at much higher rates than found in adults. They undergo metabolism for the production of Acetyl CoA, which can either enter the TCA cycle, producing NADH used by the mitochondrial electron transport chain for ATP synthesis, or for sterol synthesis, such as cholesterol, a key element for neurodevelopment signaling and essential component of membranes. KBs are preferentially used over lactate for fatty acid synthesis. (b) The astrocyte neuron lactate shuttle metabolism model is roughly represented for the adult brain metabolism scheme. Multichannel Transporters (MCRs) transport metabolites through membranes into the specified compartment.