Electrogenic aspartate/glutamate antiporter SLC25A12, mitochondrial

SLC25A12 encodes an electrogenic aspartate/glutamate antiporter localized to the mitochondrial inner membrane (UniProt: O75746). The protein functions as part of the malate-aspartate shuttle, mediating efflux of aspartate and entry of glutamate and protons into mitochondria. It also facilitates uptake of L-cysteinesulfinate in exchange for glutamate and protons, supporting mitochondrial amino acid and sulfur metabolism.

The protein is expressed in neurons and plays a critical role in mitochondrial energy metabolism and redox homeostasis. Mutations in SLC25A12 cause developmental and epileptic encephalopathy 39 with leukodystrophy (DEE39, MIM 612949), an autosomal recessive disorder characterized by refractory early-onset seizures, neurodevelopmental impairment, and hypomyelination (UniProt: O75746).

SLC25A12 is implicated in Alzheimer's Disease. In post-mortem AD brain tissue analyzed via TMT-labeled proteomics across four subcellular fractions, SLC25A12 showed ambiguous direction of change with a mean log2FC of 0.45 (Chaparral AD proteomics), suggesting differential regulation across cellular compartments or inconsistent changes between disease and control samples. This subtle alteration may reflect disrupted mitochondrial amino acid transport in AD pathology.