biostudies-literatureTavoulari SCitrin FoundationSwiss National Science FoundationMedical Research CouncilUK Research and Innovation Medical Research Council102047https://www.ebi.ac.uk/biostudies/studies/S-EPMC11539162biostudies-literatureUnknown90<h4>Objective</h4>Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency.<h4>Methods</h4>We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport actMolecular metabolismDistinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport.PMC11539162MC_UU_00028/2MC_UU_00028/5180326MC_UU_00015/7Tavoulari SPereira GCKing MSPalmer SMHe JChowdhury SRKunji ERSThangaratnarajah CLacabanne DTilokani LWalker JEPrudent JfalseDistinct roles for the domains of the mitochondrial aspartate/glutamate carrier citrin in organellar localization and substrate transport.<h4>Objective</h4>Citrin, the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), is structurally and mechanistically the most complex SLC25 family member, because it consists of three domains and forms a homo-dimer. Each protomer has an N-terminal calcium-binding domain with EF-hands, followed by a substrate-transporting carrier domain and a C-terminal domain with an amphipathic helix. The absence or dysfunction of citrin leads to citrin deficiency, a highly prevalent pan-ethnic mitochondrial disease. Here, we aim to understand the role of different citrin domains and how they contribute to pathogenic mechanisms in citrin deficiency.<h4>Methods</h4>We have employed structural modeling and functional reconstitution of purified proteins in proteoliposomes to assess the transport act2024-01-01T00:00:00Z2024 Dec2026-06-01T15:22:11.858Z2025-04-04T01:45:13.974ZS-EPMC115391623941947610.1016/j.molmet.2024.102047