PRELID1

PRELID1 is a mitochondrial intermembrane space lipid transfer protein that, in complex with TRIAP1, shuttles phosphatidic acid (PA) from the outer to the inner mitochondrial membrane, thereby fueling cardiolipin biosynthesis and sustaining mitochondrial membrane integrity (PMID:23931759). TRIAP1 binding stabilizes PRELID1 by protecting it from proteolytic degradation by IMS proteases, a regulatory mechanism conserved from yeast to mammals (PMID:20657548). PRELID1 associates with the dynamin-like GTPase OPA1 and is required for maintaining mitochondrial membrane potential, respiratory chain activity, and normal mitochondrial morphology; its loss causes cytochrome c release, elevated reactive oxygen species, and sensitization to apoptosis (PMID:21364629, PMID:23931759). In Drosophila neurons, the PRELID1 ortholog is essential for mitochondrial distribution in neurites and dendritic arbor complexity, acting upstream of Bcl-2 family–mediated cell death (PMID:19855018).

1. 2004 Medium

   Establishing that PRELID1 is a mitochondrial protein resolved the subcellular context for its function, ruling out cytosolic or ER roles.

   Evidence GFP-fusion imaging and subcellular fractionation in mammalian cells identified an N-terminal mitochondrial targeting signal

   PMID:14640972

   Open questions at the time

   • Sub-mitochondrial localization (outer membrane vs. IMS vs. matrix) not resolved
   • No functional phenotype reported
2. 2008 Medium

   Linking PRELID1 overexpression to oxidative stress, calpain activation, and STAT6 degradation in T helper cells provided the first mechanistic connection between PRELID1 and ROS-dependent signaling.

   Evidence Gain- and loss-of-function in primary human Th cells with calpain inhibitor rescue

   PMID:18945965

   Open questions at the time

   • Mechanism by which PRELID1 generates ROS not identified
   • Relevance beyond Th cells not tested
   • No lipid-level measurements
3. 2009 Medium

   In vivo loss-of-function of the Drosophila ortholog demonstrated that PRELID1 family members are essential for mitochondrial structural integrity, respiratory complex IV activity, and neuronal morphogenesis, placing the gene upstream of Bcl-2 family apoptotic regulators.

   Evidence Genetic knockout in Drosophila neurons with complex IV activity, ATP, live mitochondrial imaging, and epistasis with Drob-1/Buffy

   PMID:19855018

   Open questions at the time

   • PA/CL lipid levels not measured in fly neurons
   • Whether dendritic simplification is secondary to energy deficit or a direct lipid signaling defect is unclear
4. 2010 High

   Identifying Mdm35 (TRIAP1) as a binding partner that protects Ups1 (PRELID1) from IMS proteases established the regulatory logic controlling PRELID1 stability and, consequently, cardiolipin homeostasis.

   Evidence Co-immunoprecipitation, protease mutant epistasis (Yme1, Atp23), and protein turnover assays in yeast

   PMID:20657548

   Open questions at the time

   • Mammalian protease counterparts for PRELID1 degradation not identified
   • Stoichiometry of the TRIAP1–PRELID1 complex not determined
5. 2010 Medium

   Demonstrating that PRELID1 physically associates with OPA1 and that its LEA motif is required for maintaining membrane potential and respiratory function connected PRELID1 to mitochondrial dynamics and cristae organization.

   Evidence Co-IP of PRELI–OPA1, dominant-negative LEA-deficient mutant, membrane potential and oxygen consumption assays in mammalian cells

   PMID:21364629

   Open questions at the time

   • Whether PRELI–OPA1 interaction is direct or mediated by lipid intermediates is unresolved
   • Structural basis of the LEA motif function unknown
6. 2013 High

   Reconstituting PA transfer by the TRIAP1–PRELID1 complex in vitro established the core molecular activity: intermembrane lipid transport supplying PA for cardiolipin synthesis, linking prior genetic phenotypes to a defined biochemical function.

   Evidence In vitro lipid transfer assay between donor and acceptor liposomes, siRNA knockdown, cytochrome c release, and phosphatidylglycerol rescue in mammalian cells

   PMID:23931759

   Open questions at the time

   • Structural mechanism of PA extraction and insertion not resolved
   • Whether PRELID1 also transfers other phospholipids in vivo remains debated
7. 2017 Medium

   Identifying alternative polyadenylation as a posttranscriptional mechanism that tunes PRELID1 mRNA levels and translational output revealed how cells modulate PA transfer capacity under stress.

   Evidence PAS-seq, PRELID1 overexpression/knockdown, and mitochondrial ROS measurement

   PMID:28912168

   Open questions at the time

   • Signaling pathways that trigger the APA switch are unknown
   • Impact on cardiolipin levels not directly measured
8. 2025 Medium

   Showing that PRELID1/Ups1 preferentially extracts PA from positively curved membranes, with extraction as the rate-limiting step, provided a biophysical framework explaining how mitochondrial membrane topology regulates lipid transfer efficiency.

   Evidence In vitro lipid transfer with defined-curvature liposomes and coarse-grained MD simulations (preprint)

   PMID:bio_10.1101_2025.04.03.647039

   Open questions at the time

   • Awaits peer review
   • In vivo validation of curvature-dependent transfer not performed
   • Whether cristae curvature modulates PRELID1 activity in cells is untested
9. 2025 Medium

   Epistasis experiments placing PRELID1 downstream of the ER–mitochondria lipid transporter BLTP1 established that PRELID1-mediated PA import is required for the toxic accumulation of mitochondrial phospholipids when ER-to-OMM lipid efflux is blocked.

   Evidence PRELID1 siRNA knockdown in BLTP1-deficient cells with ROS, bioenergetics, and apoptosis readouts (preprint)

   PMID:bio_10.1101_2025.09.30.679455

   Open questions at the time

   • Awaits peer review
   • Direct measurement of PA flux in this epistasis context not shown
   • Whether other PRELID family members compensate is unknown

• A high-resolution structural mechanism for PA extraction and delivery by the TRIAP1–PRELID1 complex in the context of native mitochondrial membranes, and the physiological signals that dynamically regulate this transfer in vivo, remain to be determined.
• No high-resolution structure of the human TRIAP1–PRELID1–PA ternary complex
• In vivo real-time measurement of PA transfer rates is lacking
• Whether PRELID1 participates in inter-organelle lipid transport beyond the IMS is unknown