Abstract 2285 The guardians of mitochondrial metabolism: SoLute Carrier SLC25 family

The Solute Carrier SLC25 family consists of the largest group of mitochondrial metabolite transporters in eukaryotes, facilitating the translocation of ligands across the mitochondrial membrane. These ligands encompass a wide range of structures, including nucleotides, amino acids, carboxylic acids, and cofactors. However, a significant research gap exists because approximately 20 out of the 53 human SLC25 transporters remain poorly characterized and their regulation is largely unexplored. To address this knowledge gap, we employed a diverse array of techniques, such as CRISPR screens, cellular and mitochondrial metabolite profiling, organelle-based uptake assays, and molecular evolution approaches. Through these investigations, we uncovered the crucial role of a previously uncharacterized transporter SLC25A39 in mitochondrial glutathione transport, working in conjunction with the iron transporters to support mitochondrial oxidative phosphorylation. Building upon this finding, we combine proteomics, CRISPR and metabolite profiling, we discovered a new protein quality control mechanism that regulate the uptake of mitochondrial glutathione in response to iron availability. Using human iPSC-derived neurons, we revealed an involvement of this pathway in neurons, establishing a novel connection between cellular glutathione compartmentalization to neuronal cellular physiology. Our research on mitochondrial metabolite transporters SLC25 family have significantly advanced our understanding of fundamental aspects of mitochondrial metabolism and physiology.