A transport-independent role for SLC25A12 in mitochondrial stress signaling

Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signaling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Mutations in SLC25A13 cause a metabolic disorder, while mutations in SLC25A12 are associated with a severe neurodevelopmental condition. Here we show that SLC25A12 plays a previously unrecognized role in stress signaling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signaling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signaling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies. Overall design: To provide a broader view of the expressions for different ISR-target genes in five types of HEK293T cells with different genotypes or transfected by different cDNAs, we performed bulk RNA sequencing on these five types of cells (n=4). This allowed for the identification for regulators in ISR and relationship between ISR and mitochondrial respiration.