Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Metabolic Disorders

Background:

• Germline inactivating mutations in SLC25A1 are linked to Velocardiofacial (VCFS), DiGeorge (DGS) syndromes, and D/L-2-hydroxyglutaric aciduria (D/L-2HGA).
• The precise mechanisms underlying SLC25A1 loss-associated pathologies are not well understood.

Purpose of the Study:

• To investigate the pathogenic mechanisms of SLC25A1 deficiency using a mouse model.
• To explore the roles of senescence and p53 in D/L-2HGA and identify potential therapeutic targets.

Main Methods:

• Generation of a mouse model with Slc25a1 biallelic inactivation.
• Analysis of organ development, cellular proliferation, senescence pathways (OIS and MiDAS), and p53 activation.
• Metabolic and transcriptional profiling to identify molecular alterations.
• Intervention studies involving NAD+ replenishment and 2HG clearance.

Main Results:

• Slc25a1 deficiency in mice recapitulates VCFS/DGS and D/L-2HGA phenotypes, causing multi-organ defects and severe proliferation defects.
• Cellular senescence, driven by oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), converges on p53 activation.
• Dysfunctional SLC25A1 leads to metabolic rewiring, 2HG accumulation via a non-canonical pathway, and NAD+ depletion, triggering senescence.
• NAD+ replenishment and 2HG clearance cooperatively rescued proliferation defects.
• p53 inhibition restored proliferation, highlighting its critical role in preventing expansion of Slc25a1-deficient cells.

Conclusions:

• SLC25A1 deficiency activates senescence programs and p53, contributing to D/L-2HGA pathogenesis.
• Metabolic dysregulation, including 2HG accumulation and NAD+ depletion, are key drivers of senescence.
• Targeting senescence, p53, NAD+ metabolism, or 2HG clearance presents potential therapeutic strategies for D/L-2HGA.