PRELID3B

PRELID3B (SLMO2) is a mitochondrial intermembrane-space lipid transfer protein that shuttles phosphatidylserine (PS) from the outer to the inner mitochondrial membrane, where PS is decarboxylated to phosphatidylethanolamine, a pathway conserved from yeast (Ups2-Mdm35) through Drosophila to human and required for maintenance of mitochondrial morphology and respiratory function (PMID:27241913, PMID:39680501). Lipid binding and transfer depend on an extended, water-mediated hydrogen-bonding network within the PRELID domain; disruption of this network (R53E) releases bound lipid and abolishes transfer activity (PMID:36309326). PRELID3B partners physically with TRIAP1, and in cancer cells this interaction sustains mitochondrial membrane potential, limits reactive oxygen species, and suppresses autophagy and apoptosis (PMID:40654025); notably, the Drosophila TRIAP1 ortholog was dispensable for SLMO's role in mitochondrial morphology, indicating the morphology function can proceed independently of the partner (PMID:39680501). Loss or pharmacological inhibition of PRELID3B depletes mitochondrial phospholipids and links its activity to cellular energy and stress signaling, including overactivation of the Snf1/AMPK pathway and activation of the integrated stress response (PMID:35639425, PMID:42081720). PRELID3B is a direct binding target of the ginseng metabolite compound K and its derivative CKD-4 (PMID:42081720).

1. 2016 High

   Established the core biochemical function: whether the SLMO2-TRIAP1 (yeast Ups2-Mdm35) complex actively moves PS across the mitochondrial intermembrane space to feed inner-membrane PE synthesis.

   Evidence Yeast genetic epistasis, in vitro lipid transfer assays, mitochondrial fractionation, and respiratory and cristae imaging

   PMID:27241913

   Open questions at the time

   • Demonstrated in yeast; human complex function inferred from orthology in this study
   • Relative contributions of transfer-dependent versus trans-decarboxylation pathways in human cells not quantified
2. 2022 High

   Defined the structural basis of lipid handling: how the PRELID domain captures and releases lipid cargo during transfer.

   Evidence X-ray crystallography of apo and lipid-bound complex, molecular dynamics, R53E mutagenesis, and lipid transfer assays

   PMID:36309326

   Open questions at the time

   • Does not resolve how PS is extracted from and inserted into membranes
   • Lipid head-group selectivity determinants not fully mapped
3. 2022 Medium

   Connected the lipid-transfer function to downstream energy and cell-cycle signaling, placing PRELID3B/Ups2 upstream of AMPK/Snf1.

   Evidence Yeast ups2∆ transcriptomics and AMPK/Snf1 activity assays with sak1∆ epistasis, plus siRNA knockdown and viability assay in Rb1-deficient human cancer cells

   PMID:35639425

   Open questions at the time

   • Human data limited to a viability assay without mechanistic dissection of the AMPK link
   • How phospholipid changes mechanistically activate AMPK/Snf1 not established
4. 2024 High

   Confirmed directionality and conservation of PS transfer (OMM to IMM at the inner boundary membrane) and tested partner requirement for the morphology function.

   Evidence Drosophila forward genetic screen, PS transfer assays, electron/fluorescence microscopy, and human SLMO2 knockdown rescue

   PMID:39680501

   Open questions at the time

   • Why dTRIAP is dispensable for morphology while TRIAP1 is functionally important elsewhere unresolved
   • Spatial mechanism at the inner boundary membrane not structurally defined
5. 2025 Medium

   Showed the PRELID3B-TRIAP1 physical interaction controls mitochondrial fitness and cell survival in a disease (ovarian cancer) context.

   Evidence Co-immunoprecipitation, reciprocal knockdown/overexpression, flow cytometry of apoptosis/ROS/membrane potential, EM, and mouse xenograft

   PMID:40654025

   Open questions at the time

   • Direct PS-transfer activity in this setting inferred rather than measured
   • Whether anti-apoptotic effects are downstream of lipid transfer or a separate function unclear
6. 2026 Medium

   Identified PRELID3B as a druggable direct target whose pharmacological inhibition depletes mitochondrial phospholipids and triggers stress and immunomodulatory responses.

   Evidence PISA and ProTargetMiner proteomics, CETSA, biolayer interferometry, and multiomics in organoid and xenograft models

   PMID:42081720

   Open questions at the time

   • Single-lab study without independent replication
   • Whether compound binding directly blocks PS transfer at the structural level not shown

• How PRELID3B engages source and target membranes for PS extraction/delivery and how its lipid output is mechanistically transduced into AMPK and integrated-stress-response signaling remain unresolved.
• No structural model of the membrane-docking step
• Causal chain from phospholipid depletion to AMPK/ISR activation not delineated in human cells