Transcriptional and metabolic effects of aspartate-glutamate carrier isoform 1 (AGC1) downregulation in mouse oligodendrocyte precursor cells (OPCs).

Mitochondria Neurodevelopment Oligodendrocytes Omics analysis SLC25A12/aralar1/AGC1 deficiency White matter disorder

Journal

Cellular & molecular biology letters
ISSN: 1689-1392
Titre abrégé: Cell Mol Biol Lett
Pays: England
ID NLM: 9607427

Informations de publication

Date de publication:
29 Mar 2024
Historique:
received: 17 10 2023
accepted: 20 03 2024
medline: 30 3 2024
pubmed: 30 3 2024
entrez: 30 3 2024
Statut: epublish

Résumé

Aspartate-glutamate carrier isoform 1 (AGC1) is a carrier responsible for the export of mitochondrial aspartate in exchange for cytosolic glutamate and is part of the malate-aspartate shuttle, essential for the balance of reducing equivalents in the cells. In the brain, mutations in SLC25A12 gene, encoding for AGC1, cause an ultra-rare genetic disease, reported as a neurodevelopmental encephalopathy, whose symptoms include global hypomyelination, arrested psychomotor development, hypotonia and seizures. Among the biological components most affected by AGC1 deficiency are oligodendrocytes, glial cells responsible for myelination processes, and their precursors [oligodendrocyte progenitor cells (OPCs)]. The AGC1 silencing in an in vitro model of OPCs was documented to cause defects of proliferation and differentiation, mediated by alterations of histone acetylation/deacetylation. Disrupting AGC1 activity could possibly reduce the availability of acetyl groups, leading to perturbation of many biological pathways, such as histone modifications and fatty acids formation for myelin production. Here, we explore the transcriptome of mouse OPCs partially silenced for AGC1, reporting results of canonical analyses (differential expression) and pathway enrichment analyses, which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further investigate the cellular effects of AGC1 deficiency through the identification of most affected transcriptional networks and altered alternative splicing. Transcriptional data were integrated with differential metabolite abundance analysis, showing downregulation of several amino acids, including glutamine and aspartate. Taken together, our results provide a molecular foundation for the effects of AGC1 deficiency in OPCs, highlighting the molecular mechanisms affected and providing a list of actionable targets to mitigate the effects of this pathology.

Identifiants

pubmed: 38553684
doi: 10.1186/s11658-024-00563-z
pii: 10.1186/s11658-024-00563-z
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

44

Subventions

Organisme : Fondazione Telethon
ID : GGP19067
Organisme : Fondazione Telethon
ID : GGP19067a
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : 2022CEHEX8
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PE0000006

Informations de copyright

© 2024. The Author(s).

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Auteurs

Nicola Balboni (N)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Giorgia Babini (G)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Eleonora Poeta (E)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Michele Protti (M)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Laura Mercolini (L)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Maria Chiara Magnifico (MC)

Department of Biosciences, Biotechnologies and Environment, University of Bari, Bari, Italy.

Simona Nicole Barile (SN)

Department of Biosciences, Biotechnologies and Environment, University of Bari, Bari, Italy.

Francesca Massenzio (F)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Antonella Pignataro (A)

Department of Biosciences, Biotechnologies and Environment, University of Bari, Bari, Italy.

Federico M Giorgi (FM)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. federico.giorgi@unibo.it.

Francesco Massimo Lasorsa (FM)

Department of Biosciences, Biotechnologies and Environment, University of Bari, Bari, Italy. francesco.lasorsa@uniba.it.

Barbara Monti (B)

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. b.monti@unibo.it.

Classifications MeSH