Deficiency of Mitochondrial Aspartate-Glutamate Carrier 1 Leads to Oligodendrocyte Precursor Cell Proliferation Defects Both In Vitro and In Vivo

Abstract

Aspartate-Glutamate Carrier 1 (AGC1) deficiency is a rare neurological disease caused by mutations in the solute carrier family 25, member 12 (SLC25A12) gene, encoding for the mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), a component of the malate–aspartate NADH shuttle (MAS), expressed in excitable tissues only. AGC1 deficiency patients are children showing severe hypotonia, arrested psychomotor development, seizures and global hypomyelination. While the effect of AGC1 deficiency in neurons and neuronal function has been deeply studied, little is known about oligodendrocytes and their precursors, the brain cells involved in myelination. Here we studied the effect of AGC1 down-regulation on oligodendrocyte precursor cells (OPCs), using both in vitro and in vivo mouse disease models. In the cell model, we showed that a reduced expression of AGC1 induces a deficit of OPC proliferation leading to their spontaneous and precocious differentiation into oligodendrocytes. Interestingly, this effect seems to be related to a dysregulation in the expression of trophic factors and receptors involved in OPC proliferation/differentiation, such as Platelet-Derived Growth Factor α (PDGFα) and Transforming Growth Factor βs (TGFβs). We also confirmed the OPC reduction in vivo in AGC1-deficent mice, as well as a proliferation deficit in neurospheres from the Subventricular Zone (SVZ) of these animals, thus indicating that AGC1 reduction could affect the proliferation of different brain precursor cells. These data clearly show that AGC1 impairment alters myelination not only by acting on N-acetyl-aspartate production in neurons but also on OPC proliferation and suggest new potential therapeutic targets for the treatment of AGC1 deficiency.

Glutamate Carrier Involvement in Mitochondrial Dysfunctioning in the Brain White Matter

“…In line with this, AGC1 deficiency leads to decreased OPC proliferation (Petralla et al, 2019) and also to myelin deficits considering its function in the MAS (Wibom et al, 2009). The OPC maturation defects in VWM and AxD (Li et al, 2018;Leferink et al, 2019) could be associated to dysfunction of mitochondria, and specifically of AGC1 (Petralla et al, 2019). The MAS function of AGCs furthermore regulates the balance of glycolysis in the cytosol and oxidative phosphorylation in the mitochondrion (Lasorsa et al, 2003;Kasai et al, 2019).…”

“…Myelination requires mitochondrial production of acetyl-CoA, metabolized from neuronal aspartate (Dahlin et al, 2015), which is supported by oligodendrocyte lineage cell activity that increases mitochondrial ATP production and mitochondrial transcript levels (Silva et al, 2009;Schoenfeld et al, 2010). In line with this, AGC1 deficiency leads to decreased OPC proliferation (Petralla et al, 2019) and also to myelin deficits considering its function in the MAS (Wibom et al, 2009). The OPC maturation defects in VWM and AxD (Li et al, 2018;Leferink et al, 2019) could be associated to dysfunction of mitochondria, and specifically of AGC1 (Petralla et al, 2019).…”

“…AGC1 deficiency is associated with epilepsy (Falk et al, 2014), hypomyelination (Wibom et al, 2009), and reduced NAA (Jalil et al, 2005;Falk et al, 2014;Profilo et al, 2017), which is an important substrate for myelin lipids. Furthermore, oligodendrocyte precursor cell (OPC)-specific AGC1 deficiency resulted in inhibited proliferation and increased maturation, suggesting an interactive pathway between AGC1 and oligodendrocytes in addition to the provision of NAA (Petralla et al, 2019).…”

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

“…In fact, mice lacking AGC1 display growth retardation, an impaired central nervous system function, and reduced brain levels of N-acetyl-aspartate [96]. Moreover, AGC1 depletion in neurons (Neuro2A cells) and oligodendrocytes (precursor cells) inhibits proliferation and N-acetylaspartate synthesis [97,98]. It is noteworthy that (i) single nucleotide polymorphisms in AGC1 have been suggested to be associated with multi-factorial disorders, such as autism [99], and (ii) a mutation in AGC1 of Dutch shepherd dogs causes reduced transport activity of aspartate and glutamate in reconstituted liposomes as well as inflammatory myopathy [100].…”

Amino Acids Transport and Metabolism 2.0

“…As an example, the review by Monnè et al focuses on the role played, in energy production, by mitochondrial carriers involved in the transport of amino acids; notably, the defects of these carriers, caused by inherited mutations, are responsible for a series of human diseases [19]. The article by Petralla et al describes the link between AGC1 (aspartate/glutamate carrier 1) deficiency with neurological disorders by using in vitro and in vivo mouse disease models [20]. Lastly, the article by Traustason et al deals with the employment of computational strategies for the optimization of the amino acid composition of cell growth media.…”