SLC25A22 encodes a mitochondrial glutamate/H+ symporter responsible for transporting glutamate from the cytosol into the mitochondrial matrix 1. The transporter functions bidirectionally, with capacity to export glutamate from mitochondria to cytosol under certain metabolic conditions 2. Mechanism: SLC25A22 facilitates glutaminolysis, the conversion of glutamine to tricarboxylic acid cycle intermediates including α-ketoglutarate and succinate 3. In KRAS-mutant colorectal cancer cells, SLC25A22 promotes aspartate synthesis by maintaining oxaloacetate levels, supporting both energy production and nucleotide biosynthesis 4. The transporter also modulates glutathione and proline synthesis, which promote antioxidant defense and extracellular matrix remodeling respectively 2. Disease Relevance: SLC25A22 mutations cause developmental and epileptic encephalopathy, including migrating partial seizures in infancy and neonatal epilepsy with suppression bursts 5. Loss-of-function mutations (p.G110R, p.Lys33Glu) disrupt mitochondrial glutamate transport 56. SLC25A22 downregulation associates with Alzheimer's disease onset and hippocampal atrophy 7. Clinical Significance: SLC25A22 overexpression promotes malignant progression in colorectal cancer, osteosarcoma, cervical squamous cell carcinoma, and glioblastoma, correlating with poor prognosis 489. SLC25A22 inhibition enhances immunotherapy efficacy and chemotherapy sensitivity, suggesting therapeutic potential 392.