PRELID1

PRELID1 (PRELI) is a mitochondrial intermembrane-space lipid transfer protein that controls cardiolipin homeostasis and thereby sets the threshold for mitochondrial apoptosis (PMID:23931759). It forms a complex with TRIAP1 that extracts phosphatidic acid and transfers it across the IMS to the inner membrane for cardiolipin synthesis; loss of PRELID1 impairs cardiolipin accumulation, facilitates cytochrome c release, and sensitizes cells to apoptosis, with survival rescued by exogenous phosphatidylglycerol (PMID:23931759). PRELID1 is targeted to mitochondria by an N-terminal mitochondrial targeting signal (PMID:14640972). Work on the yeast ortholog Ups1 established the conserved logic of this pathway: Ups1 is an intrinsically unstable IMS protein whose stability and import are protected by binding the twin Cx9C protein Mdm35 (TRIAP1 in mammals), with turnover executed by the proteases Atp23 and Yme1 (PMID:20657548), and its phosphatidic-acid extraction is rate-limited by donor-membrane events, favored at positively curved membrane domains and tuned by pH and lipid composition [PMID:bio_10.1101_2025.04.03.647039]. Consistent with its role in cardiolipin-driven death, PRELID1 acts downstream of BLTP1-mediated phospholipid efflux: depleting PRELID1 blocks the pathological cardiolipin accumulation and apoptosis caused by BLTP1 loss [PMID:bio_10.1101_2025.09.30.679455]. Beyond cardiolipin transfer, PRELID1 associates with the dynamin-like GTPase OPA1 and supports mitochondrial morphology, membrane potential, and respiratory chain function in a manner requiring its LEA motif (PMID:21364629), and it modulates mitochondrial ROS and apoptotic/senescence responses across cell types (PMID:18945965, PMID:26275693).

1. 2004 Medium

   Establishing where PRELI acts was the first step; demonstrating mitochondrial residence framed all subsequent mechanistic work.

   Evidence GFP-fusion live imaging and subcellular fractionation identifying an N-terminal mitochondrial targeting signal

   PMID:14640972

   Open questions at the time

   • Did not resolve sub-mitochondrial localization (IMS vs matrix)
   • No functional role assigned
2. 2010 High

   Yeast genetics resolved how the unstable PRELI/Ups1 protein is stabilized and degraded, defining the chaperone-protease control of cardiolipin regulation.

   Evidence Yeast genetic epistasis, reciprocal Ups1/Mdm35 co-IP, and protease mutant (Δyme1, Δatp23) turnover analysis

   PMID:20657548

   Open questions at the time

   • Did not directly demonstrate lipid transfer biochemistry
   • Mammalian protease equivalents not tested here
3. 2010 Medium

   A parallel line tied PRELI to OPA1 and bioenergetics, linking it to mitochondrial morphology and respiratory function beyond a purely structural role.

   Evidence PRELI–OPA1 co-IP, dominant-negative LEA(-) mutant, siRNA knockdown with ΔΨm/O2/ROS/complex readouts, and mouse embryo lethality

   PMID:21364629

   Open questions at the time

   • OPA1 interaction not validated structurally or by reconstitution
   • Dominant-negative approach carries interpretive caveats
4. 2013 High

   The central mechanism was defined: PRELI/TRIAP1 directly transfers phosphatidic acid for cardiolipin synthesis, mechanistically coupling lipid handling to apoptosis sensitivity.

   Evidence TRIAP1/PRELI co-IP, in vitro lipid transfer assay, siRNA loss-of-function with CL/cytochrome c/apoptosis measurement, and phosphatidylglycerol rescue

   PMID:23931759

   Open questions at the time

   • Structural basis of PA binding not resolved
   • Regulation of transfer in cells not defined
5. 2017 Low

   Post-transcriptional control was identified, showing alternative polyadenylation raises PRELID1 levels and links it to cell-type-specific ROS regulation.

   Evidence PAS-seq in breast tumor specimens with PRELID1 modulation and mitochondrial ROS measurement

   PMID:28912168

   Open questions at the time

   • Molecular mechanism of ROS regulation not defined beyond inference to the PA/CL pathway
   • Single-lab correlative tumor data
6. 2025 Medium

   Genetic epistasis placed PRELID1 in a defined lipid-flux circuit, showing it is required downstream of BLTP1 for pathological cardiolipin accumulation and apoptosis.

   Evidence Double depletion of BLTP1 and PRELID1 with PA/PG/CL, apoptosis, and ROS measurement (preprint)

   PMID:bio_10.1101_2025.09.30.679455

   Open questions at the time

   • Preprint, not peer-reviewed
   • Direct physical relationship between BLTP1 and PRELID1 not established
7. 2025 Medium

   Biophysical reconstitution refined the transfer mechanism, showing donor-membrane curvature is the rate-limiting determinant of PA extraction.

   Evidence In vitro lipid transfer with curvature-defined membranes, biophysical binding, and MD modeling (preprint)

   PMID:bio_10.1101_2025.04.03.647039

   Open questions at the time

   • Preprint, not peer-reviewed
   • Performed on yeast Ups1; mammalian PRELID1 curvature preference not confirmed

• How PRELID1's lipid transfer activity, OPA1 association, and ROS/apoptosis outputs are integrated and regulated in mammalian cells remains unresolved.
• No structural model of mammalian PRELID1/TRIAP1 bound to PA
• Mechanism connecting cardiolipin transfer to OPA1-dependent morphology unclear
• In vivo physiological role beyond embryonic lethality uncharacterized