Fundamentals of CNS energy metabolism and alterations in lysosomal storage diseases

Abstract

The brain has a very high requirement for energy. Adult brain relies on glucose as an energy substrate, whereas developing brain can utilize alternative substrates as well as glucose for energy and for the biosynthesis of lipids and proteins required for brain development. Metabolism provides the energy required to support all cellular functions and brain development and building blocks for macromolecules. Lysosomes are organelles involved in breakdown of biological compounds including proteins and complex lipids in the body and brain. Recent studies suggest that lysosomal dysfunction can damage neurons and/or alter neurotransmitter homeostasis. Several studies also implicate mitochondrial dysfunction in the pathophysiology of brain damage in lysosomal storage diseases. This manuscript provides a brief review of energy metabolism and the key pathways involved in metabolism in brain. Roles of lysosomes related to metabolism and neurotransmission are discussed, and evidence for mitochondrial dysfunction in several lysosomal storage diseases is presented. This article is part of the Special Issue "Lysosomal Storage Disorders".

Lysosomal storage disorders: pathology within the lysosome and beyond

“…describes the fundamentals of brain metabolism with implications of energy imbalances in the context of LSDs (McKenna et al . ). The brain has an extremely high energy demand and an interesting dichotomy exists with regard to metabolic substrates utilized by the developing versus adult brain.…”

“…Specifically, the adult brain has an absolute requirement for glucose, whereas the developing brain is able to utilize a number of metabolic substrates in addition to glucose, including lactate, amino acids, ketone bodies, fatty acids, and glycerol (McKenna et al . ). The diversity of metabolic substrates capable of supporting brain development may account for the delayed clinical presentation of several LSDs that affect the CNS by compensating for lysosomal dysfunction, although this possibility remains speculative.…”

“…), CNS metabolism (McKenna et al . ), and sphingolipid biosynthesis and turnover (Grassi et al . ), all of which are critical toward our understanding of normal lysosomal function and how this is perturbed in the context of LSDs.…”

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

“…2f). This is a plausible result considering that these pathways are essential for normal brain development [30, 31]. To summarize, these observations suggest that gene properties are stronger determinants of whether the disease adopts a recessive or dominant inheritance pattern than variant properties.…”

Linking lysosomal enzyme targeting genes and energy metabolism with altered gray matter volume in children with persistent stuttering

“…This link could be mediated through mutations in metabolic genes as candidates in persistent stuttering. However, it is also possible that the GMV differences between pCWS and controls were exacerbated in brain regions with relatively high energy consumption related to disturbance in lysosomal function (McKenna, Schuck, & Ferreira, 2018).…”