Glutamate Carrier Involvement in Mitochondrial Dysfunctioning in the Brain White Matter

Anne E J Hillen; Vivi M Heine

doi:10.3389/fmolb.2020.00151

Glutamate Carrier Involvement in Mitochondrial Dysfunctioning in the Brain White Matter

Front Mol Biosci. 2020 Jul 21:7:151. doi: 10.3389/fmolb.2020.00151. eCollection 2020.

Authors

Anne E J Hillen¹, Vivi M Heine^{2

3}

Affiliations

¹ Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
² Child and Youth Psychiatry, Emma Children's Hospital, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
³ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Abstract

Glutamate homeostasis is an important determinant of health of the central nervous system (CNS). Mitochondria play crucial roles in glutamate metabolism, especially in processes with a high energy demand such as action potential generation. Mitochondrial glutamate carriers (GCs) and aspartate-GCs (AGCs) regulate the transport of glutamate from the cytoplasm across the mitochondrial membrane, which is needed to control energy demand, lipid metabolism, and metabolic activity including oxidative phosphorylation and glycolysis. Dysfunction in these carriers are associated with seizures, spasticity, and/or myelin deficits, all of which are associated with inherited metabolic disorders. Since solute carrier functioning and associated processes are cell type- and context-specific, selective vulnerability to glutamate excitotoxicity and mitochondrial dysfunctioning is expected. Understanding this could offer important insights into the pathomechanisms of associated disorders. This perspective aims to explore the link between functions of both AGCs and GCs and their role in metabolic disorders, with a focus on a subclass of lysosomal storage disorders called leukodystrophies (LDs).

Keywords: aspartate-glutamate carriers; cell metabolism; cell type specificity; excitotoxicity; glutamate carriers; leukodystrophy; mitochondria; white matter.