SLC25A23

SLC25A23 (SCaMC-3) is an EF-hand-containing mitochondrial solute carrier that couples calcium handling to mitochondrial redox and cell-death signaling (PMID:15716113, PMID:24430870). The protein has a bipartite architecture—an N-terminal region with three canonical EF-hand Ca2+-binding domains and a C-terminal mitochondrial carrier domain—localizes to mitochondria, and binds calcium directly (PMID:15716113). It augments mitochondrial Ca2+ uptake by interacting with the MCU uniporter and MICU1; its EF-hand domains are functionally required, as EF-hand mutants act as dominant negatives and knockdown reduces both mitochondrial Ca2+ uptake and downstream superoxide production (PMID:24430870). Through this calcium-handling role, SLC25A23 supports basal mitochondrial ROS accumulation, oxidant-induced ATP decline, and cell death, and its suppression elevates ROS and triggers JNK-dependent death-receptor-5 upregulation and selective death of senescent cancer cells (PMID:24430870, PMID:39693343). Independently of its carrier function, SLC25A23 negatively regulates innate antiviral immunity: it binds the E3 ligase Trim31 and blocks Trim31-mediated K63-linked polyubiquitination and aggregation of MAVS, so that its loss enhances type I interferon production and confers resistance to RNA virus infection in vivo (PMID:37695673).

1. 2005 Medium

   Established the basic identity of SLC25A23 as a mitochondrial calcium-binding carrier, defining the bipartite EF-hand/carrier architecture that would later explain its calcium-handling role.

   Evidence Transfection/localization imaging in HeLa cells and Ca2+-dependent mobility shift assay, with tissue expression and splicing analysis

   PMID:15716113

   Open questions at the time

   • Did not demonstrate a transport substrate for the carrier domain
   • No functional link to a calcium-handling pathway established at this stage
2. 2005 Low

   A yeast two-hybrid screen flagged SLC25A23 as a candidate binding partner of hepatitis B virus S protein, raising an early but unvalidated host-pathogen connection.

   Evidence Yeast two-hybrid screen of a human liver cDNA library

   PMID:15991290

   Open questions at the time

   • Single Y2H hit with no biochemical or cellular validation
   • Interaction never confirmed by co-IP or functional assay
   • No mechanistic consequence of the interaction defined
3. 2014 High

   Placed SLC25A23 mechanistically within the mitochondrial calcium uptake machinery, showing it physically engages the MCU-MICU1 complex and that its EF-hands are required to drive uptake.

   Evidence Reciprocal co-IP with MCU and MICU1, shRNA knockdown, EF-hand dominant-negative mutagenesis, and shRNA-insensitive reconstitution with Ca2+ uptake assays

   PMID:24430870

   Open questions at the time

   • Stoichiometry and architecture of the SLC25A23-MCU-MICU1 assembly not resolved
   • Whether SLC25A23 transports a metabolite while modulating uptake unaddressed
4. 2014 Medium

   Connected SLC25A23-dependent mitochondrial Ca2+ uptake to downstream physiology, linking it to mitochondrial ROS, ATP balance, and oxidant-induced cell death.

   Evidence shRNA knockdown with mROS, ATP, and cell death readouts

   PMID:24430870

   Open questions at the time

   • Causal chain from Ca2+ uptake to ROS to death not dissected step-by-step
   • Cell-type generality of the death phenotype untested
5. 2023 High

   Revealed a moonlighting, transport-independent role: SLC25A23 restrains antiviral signaling by sequestering Trim31 away from MAVS, defining it as a negative regulator of type I interferon.

   Evidence Genome-wide CRISPR screen, co-IP of SLC25A23-Trim31, K63-ubiquitination and MAVS aggregation assays, IFN readouts, and viral challenge in knockdown mice

   PMID:37695673

   Open questions at the time

   • Whether the antiviral role depends on mitochondrial Ca2+/carrier activity is unresolved
   • Structural basis of the SLC25A23-Trim31 interaction unknown
6. 2024 Medium

   Identified SLC25A23 as a selective vulnerability of senescent cancer cells, tying its calcium/redox function to a JNK-DR5 death axis.

   Evidence CRISPR/Cas9 screen with SLC25A23 suppression and calcium, OXPHOS, ROS, JNK, and DR5 readouts

   PMID:39693343

   Open questions at the time

   • Mechanism linking calcium disruption to JNK activation not fully defined
   • Single-lab finding without orthogonal genetic confirmation

• It remains unknown what metabolite the C-terminal carrier domain transports and whether the mitochondrial calcium and antiviral/Trim31 functions are mechanistically coupled or independent.
• No transported substrate identified for the carrier domain
• No structural model of SLC25A23 in any complex
• Relationship between calcium-handling and Trim31-MAVS functions unresolved