{"gene":"LRPPRC","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2011,"finding":"LRPPRC forms an RNA-dependent protein complex necessary for maintaining a pool of non-translated mitochondrial mRNAs; loss of LRPPRC decreases mRNA stability, abolishes mRNA polyadenylation, and causes aberrant (misregulated) mitochondrial translation, including excessive translation of some transcripts and no translation of others.","method":"Conditional Lrpprc knockout mice (heart-specific); steady-state mRNA analysis, polyadenylation assays, mitochondrial translation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo conditional KO with multiple orthogonal molecular readouts (mRNA stability, polyadenylation, translation profiling)","pmids":["22045337"],"is_preprint":false},{"year":2006,"finding":"LRP130 (LRPPRC) is a component of the PGC-1α transcriptional coactivator holocomplex in the nucleus and regulates expression of gluconeogenic genes (PEPCK, G6P) and certain mitochondrial genes through PGC-1α; adenoviral RNAi knockdown of LRP130 in fasted mice blocks induction of PEPCK and G6P and blunts hepatic glucose output.","method":"Co-immunoprecipitation/mass spectrometry of PGC-1α complex; adenoviral RNAi knockdown in mice; gene expression analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying complex + in vivo KD with defined metabolic phenotype","pmids":["17050673"],"is_preprint":false},{"year":2010,"finding":"LRPPRC is exclusively localized to the mitochondrial matrix in mammalian cells; it is imported into the matrix with cleavage of its mitochondrial targeting sequence upon entry, and orthologous proteins in metazoans all contain mitochondrial targeting signals.","method":"Subcellular fractionation, bioinformatic analysis of mitochondrial targeting signals, direct localization experiments in mammalian cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — direct fractionation experiment with functional localization determination, supported by bioinformatics","pmids":["20633537"],"is_preprint":false},{"year":2010,"finding":"RNAi-mediated knockdown of LRPPRC specifically reduces steady-state levels of all mitochondrial DNA-encoded mRNAs but not mitochondrial rRNAs, establishing a specific role for LRPPRC in mtDNA-encoded mRNA expression.","method":"Stable RNAi knockdown allelic series in cells; genome-wide expression profiling with gene set enrichment analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic perturbation with multiple knockdown levels and genome-wide readout","pmids":["20220140"],"is_preprint":false},{"year":2017,"finding":"The LRPPRC–SLIRP complex functions as a global RNA chaperone that stabilizes RNA secondary structures throughout the mitochondrial transcriptome (preferentially mRNAs), exposing sites required for translation, stabilization, and polyadenylation; loss of LRPPRC affects the entire secondary structure and stability of the mitochondrial transcriptome.","method":"RNase footprinting combined with PAR-CLIP at high depth; loss-of-function analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — deep RNase footprinting + PAR-CLIP providing transcriptome-wide structural data, replicated in loss-of-function context","pmids":["29146908"],"is_preprint":false},{"year":2015,"finding":"SLIRP stabilizes LRPPRC by protecting it from degradation; SLIRP is completely dependent on LRPPRC for its own stability; SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs but is required for proper association of mRNAs with the mitochondrial ribosome and efficient translation.","method":"Slirp knockout mice; RNA sequencing of mitochondrial ribosomal fractions; molecular analyses of mRNA polyadenylation and translation","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo KO mice with multiple molecular readouts distinguishing SLIRP vs. LRPPRC functions","pmids":["26247782"],"is_preprint":false},{"year":2016,"finding":"LRPPRC and SLIRP form a stable heterodimer via interactions between three neighbouring PPR motifs in the second quarter of LRPPRC and the single RRM domain of SLIRP; residues predicted to contact RNA in both proteins are instead used for protein–protein interactions at the binding interface.","method":"In vitro RNA binding assays; mutagenesis of interface residues; biochemical characterization of the heterodimer","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis defining molecular interface","pmids":["27353330"],"is_preprint":false},{"year":2014,"finding":"Loss of LRPPRC in conditional knockout mouse hearts causes impaired mitochondrial respiration and reduced ATP production primarily through an ATP synthase (complex V) deficiency, not only COX deficiency; inactive subassembled ATP synthase complexes cause mitochondrial hyperpolarization and increased ROS production.","method":"Conditional Lrpprc cardiac knockout mice; measurement of respiratory chain complex activities, ATP production, mitochondrial membrane potential, ROS","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple biochemical readouts revealing unexpected pathway (ATP synthase vs. COX)","pmids":["24399447"],"is_preprint":false},{"year":2011,"finding":"LRP130 (LRPPRC) complexes with the mitochondrial RNA polymerase (POLRMT) to activate mitochondrial transcription, which is associated with increased OXPHOS activity, increased respiratory supercomplexes, denser cristae, and elevated ATP; LRP130 also increases hepatic β-fatty acid oxidation.","method":"Genetic and biochemical approaches; co-immunoprecipitation of LRP130 with POLRMT; measurement of OXPHOS activity, ATP, supercomplexes, fatty acid oxidation using 14C-palmitate","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional metabolic assays in single study; partially contradicted by later work (PMID 23599432)","pmids":["21971050"],"is_preprint":false},{"year":2013,"finding":"LRPPRC does not directly interact with POLRMT or activate mtDNA transcription; variation in LRPPRC levels in vivo affects unprocessed mitochondrial precursor transcripts but not steady-state transcript levels or de novo transcription; LRPPRC acts exclusively as a post-transcriptional regulator.","method":"BAC transgenic mice with increased LRPPRC; heterozygous Lrpprc KO mice; size exclusion chromatography; co-immunoprecipitation; in vitro transcription system with purified LRPPRC","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution assay, in vivo genetic models, and Co-IP all converge on same conclusion","pmids":["23599432"],"is_preprint":false},{"year":2012,"finding":"LRPPRC binds directly to a specific segment of COX1 mRNA (mouse mtDNA nucleotides 5961–6020) via its first 19 PPR motifs, and this binding stabilizes mitochondrial mRNA transcripts encoding COX subunits; homozygous LRPPRC disruption causes embryonic lethality and major COX activity decrease in MEFs.","method":"Gene-trap mouse model; RNA binding assays with recombinant LRPPRC truncation constructs containing different numbers of PPR motifs; biochemical measurement of respiratory chain complex activities","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro RNA binding reconstitution with deletion mapping + in vivo mouse model","pmids":["21880015"],"is_preprint":false},{"year":2014,"finding":"LRPPRC forms a ribonucleoprotein complex with SLIRP that stabilizes polyadenylated mitochondrial mRNAs; LSFC founder mutation reduces LRPPRC levels in a tissue-specific manner, leading to tissue-specific patterns of OXPHOS deficiency (combined complex I+IV in muscle, severe complex IV loss in liver).","method":"Analysis of LSFC patient-derived cell lines and tissues; BN-PAGE; measurement of OXPHOS complex activities; LRPPRC/SLIRP levels by western blot","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple patient tissues with orthogonal biochemical methods","pmids":["25214534"],"is_preprint":false},{"year":2024,"finding":"LRPPRC functions as an mRNA delivery factor that recruits mitochondrial mRNAs to the mitoribosome; cryo-EM structure of the LRPPRC–SLIRP–mRNA–mitoribosome complex shows LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 through its helical repeats, forming a corridor for mRNA handoff; SLIRP directly binds mRNA and stabilizes LRPPRC; LRPPRC-SLIRP has transcript-specific influence on mRNA translation efficiency, with COX1 and COX2 translation most affected.","method":"Cryo-electron microscopy structure determination; RNA sequencing; metabolic labeling; mitoribosome profiling","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with functional validation by metabolic labeling and ribosome profiling","pmids":["39134711"],"is_preprint":false},{"year":2013,"finding":"LRPPRC associates with mitochondria, interacts with Beclin 1 and Bcl-2, and forms a ternary complex to maintain Bcl-2 stability; suppression of LRPPRC reduces mitochondrial potential and Bcl-2 levels, releasing Beclin 1 to form the Beclin1–PI3KCIII complex and activating autophagy upstream of ATG5-ATG12-mediated LC3-I to LC3-II conversion.","method":"Co-immunoprecipitation of LRPPRC–Beclin1–Bcl-2 complex; LRPPRC knockdown in multiple cell lines; autophagy markers (GFP-LC3 puncta, LC3-II, p62); PI3K/Akt/mTOR pathway analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifying ternary complex + multiple cellular autophagy readouts, single lab","pmids":["23822101"],"is_preprint":false},{"year":2014,"finding":"LRPPRC maintains the stability of Parkin (which mono-ubiquitinates Bcl-2 to increase Bcl-2 stability and inhibit autophagy); under mitophagy stress, Parkin translocates to mitochondria, binds exposed LRPPRC on ruptured outer mitochondrial membrane, and LRPPRC together with Parkin promotes engulfment of mitochondria into autophagosomes.","method":"Co-immunoprecipitation of LRPPRC–Parkin; mitophagy stress assays; immunofluorescence of Parkin translocation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus live-cell imaging, single lab","pmids":["24722279"],"is_preprint":false},{"year":2008,"finding":"LRP130 is a component of PGC-1α coactivator complexes in brown adipocytes; LRP130 is preferentially enriched in brown versus white fat and is induced in a PGC-1-dependent manner during differentiation; brown fat cells deficient for LRP130 show attenuated expression of UCP1 and reduced proton leak.","method":"ShRNA knockdown of LRP130 in brown adipocytes; oxygen consumption assays; gene expression analysis; PGC-1α coactivator complex binding","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — KD with metabolic phenotype + PGC-1α complex association, single lab","pmids":["18728005"],"is_preprint":false},{"year":2017,"finding":"Loss of hepatic LRPPRC causes severe complex IV and ATP synthase assembly defects, impairs long-chain fatty acid oxidation, dysregulates the mitochondrial permeability transition pore, and alters trans-membrane H2O2 diffusion; the H2O2 alteration is traced to ATP synthase assembly defect and changes in mitochondrial membrane lipid composition.","method":"Hepatocyte-specific Lrpprc knockout mice; mitochondrial phenotyping including OXPHOS complex activities, ultrastructure, fatty acid oxidation, permeability transition pore assays, ROS measurements","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo KO with comprehensive mitochondrial phenotyping across multiple orthogonal assays","pmids":["28575497"],"is_preprint":false},{"year":2004,"finding":"LRP130 (LRPPRC) binds to the invMED1 cis-activating element in the promoters of MDR1 and MVP genes in the nucleus and is involved in transcriptional activation of these multidrug resistance-related genes; its binding intensity increases with MDR1 expression.","method":"Electrophoretic mobility shift assay; siRNA knockdown; transcriptional decoy experiments; nuclear factor identification","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2–3 — DNA binding assay + siRNA with functional gene expression readout, single lab","pmids":["15272088"],"is_preprint":false},{"year":2020,"finding":"LRPPRC forms a transcriptional repressor complex with PGC1α on the FOXO4 promoter; lncRNA GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promoter, thereby suppressing FOXO4 and p21 expression and preventing cellular senescence.","method":"Co-immunoprecipitation of LRP130–PGC1α complex; ChIP at FOXO4 promoter; siRNA knockdown of LRP130/PGC1α; senescence assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP + ChIP + functional senescence readout, single lab","pmids":["32149459"],"is_preprint":false},{"year":2022,"finding":"LRPPRC binds to CDK6 mRNA, increasing its stability and protein expression; CDK6 and its downstream effector E2F1 bind to the LRPPRC promoter and elevate LRPPRC transcription, forming a positive feedback LRPPRC–CDK6 loop that promotes G1/S transition, oxidative phosphorylation, and cancer stem cell generation.","method":"RNA immunoprecipitation (RIP) showing LRPPRC–CDK6 mRNA binding; mRNA stability assays; ChIP showing CDK6/E2F1 at LRPPRC promoter; functional cell cycle, OXPHOS, and stem cell assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — RIP, mRNA stability assay, ChIP, and functional rescue experiments in single study","pmids":["37452037"],"is_preprint":false},{"year":2022,"finding":"LRPPRC acts as an m6A reader that binds the m6A modification site of MDR1 mRNA and enhances MDR1 mRNA stability and protein expression; P53 normally suppresses LRPPRC via miR-34a; when P53 is mutated, LRPPRC and MDR1 accumulate, promoting chemoresistance.","method":"RIP assays; RNA stability assays; miR-34a/LRPPRC/MDR1 pathway analysis; in vitro and in vivo functional assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP demonstrating m6A-dependent mRNA binding + functional pathway validation, single lab","pmids":["35484333"],"is_preprint":false},{"year":2023,"finding":"LRPPRC functions as an m6A reader that posttranscriptionally upregulates PD-L1 mRNA stability in an m6A-dependent manner in hepatocellular carcinoma, promoting immune evasion.","method":"RIP, MeRIP-qPCR, RNA stability assays, xenograft tumor models, immunohistochemical staining","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple RNA biochemistry methods demonstrating m6A reading function, single lab","pmids":["37063837"],"is_preprint":false},{"year":2024,"finding":"LRPPRC promotes glycolysis in triple-negative breast cancer by recognizing the m6A site of LDHA mRNA and enhancing LDHA mRNA stability; LRPPRC knockdown reduces glycolysis while glutaminolysis is enhanced, creating synthetic lethality when combined with glutaminase inhibition.","method":"MeRIP-sequencing, RNA-immunoprecipitation, RNA pull-down, RNA stability assays, Seahorse metabolic assays, patient-derived xenografts and organoids","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 1–2 — MeRIP-seq + multiple RNA biochemistry methods identifying LDHA as direct m6A target, single lab","pmids":["38372449"],"is_preprint":false},{"year":2012,"finding":"LRPPRC associates with HIV-1 nucleic acids during early infection (co-immunoprecipitation RT-PCR); knockdown of LRPPRC reduces preintegration complex formation and viral DNA nuclear import, identifying LRPPRC as a host factor required for early steps of HIV-1 replication.","method":"Co-immunoprecipitation RT-PCR; stable LRPPRC knockdown cell lines; subcellular fractionation; viral replication assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP demonstrating LRPPRC–viral nucleic acid association + KD with defined replication defects, single lab","pmids":["22808186"],"is_preprint":false},{"year":2022,"finding":"Influenza A (H1N1)pdm09 NS1 protein directly interacts with LRPPRC and competitively blocks the interaction of LRPPRC with BECN1, thereby releasing BECN1 to activate PIK3C3 and induce autophagy initiation, promoting viral replication.","method":"Co-immunoprecipitation; competitive binding assays; LRPPRC knockout cell lines; autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP demonstrating competitive displacement of BECN1 from LRPPRC + KO validation, single lab","pmids":["36300799"],"is_preprint":false},{"year":2022,"finding":"PSMD14 deubiquitinase directly interacts with LRPPRC and inhibits its ubiquitination, thereby stabilizing LRPPRC protein; stabilized LRPPRC in turn suppresses autophagy through the LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway in ovarian cancer.","method":"Co-immunoprecipitation of PSMD14–LRPPRC; ubiquitination assays; autophagy marker analysis; in vivo xenograft models","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifying deubiquitinase–substrate interaction + functional autophagy readout, single lab","pmids":["36328147"],"is_preprint":false}],"current_model":"LRPPRC is a mitochondrial matrix PPR-protein that, in complex with SLIRP, functions as a global RNA chaperone and mRNA delivery factor: it stabilizes mitochondrial mRNA secondary structures, promotes their polyadenylation, maintains a pool of non-translated mRNAs, and physically recruits mRNAs to the mitoribosome (via contacts with mS39/mS31) for translation, with transcript-specific effects particularly on COX1/COX2; outside mitochondria, LRPPRC can act in the nucleus as part of PGC-1α coactivator complexes to regulate gluconeogenic and brown-fat genes, and functions as an m6A reader to stabilize cytoplasmic mRNAs (including MDR1, LDHA, PD-L1), while also suppressing autophagy initiation by maintaining a Bcl-2–Beclin1 inhibitory complex."},"narrative":{"teleology":[{"year":2004,"claim":"The initial identification of LRPPRC as a nuclear DNA-binding factor at the MDR1 promoter raised the question of whether it functions in gene regulation beyond mitochondria.","evidence":"EMSA and siRNA knockdown linking LRP130 to invMED1-dependent transcriptional activation of MDR1/MVP","pmids":["15272088"],"confidence":"Medium","gaps":["Nuclear DNA-binding function not independently replicated","Relationship to predominant mitochondrial localization unresolved","No structural basis for DNA recognition"]},{"year":2006,"claim":"Discovery that LRPPRC is a stable component of the PGC-1α transcriptional coactivator complex established its role in nuclear transcriptional regulation of gluconeogenic and mitochondrial genes, answering how hepatic glucose output is coordinated with mitochondrial biogenesis.","evidence":"Co-IP/mass spectrometry of PGC-1α complex; adenoviral RNAi in fasted mice showing blunted PEPCK/G6P induction","pmids":["17050673"],"confidence":"High","gaps":["Mechanism by which LRPPRC partitions between nucleus and mitochondria unknown","Direct vs. indirect effect on PGC-1α target promoters not distinguished"]},{"year":2010,"claim":"Definitive localization of LRPPRC to the mitochondrial matrix and demonstration that its loss selectively reduces all mtDNA-encoded mRNAs (but not rRNAs) resolved the primary site of action and established transcript-class specificity.","evidence":"Subcellular fractionation and MTS cleavage analysis; RNAi allelic series with genome-wide expression profiling","pmids":["20633537","20220140"],"confidence":"High","gaps":["Mechanism of mRNA selectivity over rRNA unknown","Whether a dual nuclear-mitochondrial pool exists in vivo remained debated"]},{"year":2011,"claim":"Conditional knockout in mouse hearts revealed that LRPPRC maintains a pool of non-translated polyadenylated mRNAs and that its loss abolishes polyadenylation while causing globally dysregulated mitochondrial translation, establishing LRPPRC as a post-transcriptional coordinator rather than simply a stabilizer.","evidence":"Heart-specific Lrpprc KO mice; mRNA polyadenylation assays and metabolic labeling of mitochondrial translation","pmids":["22045337"],"confidence":"High","gaps":["How LRPPRC coordinates polyadenylation machinery mechanistically unclear","Transcript-specific translation effects not fully explained"]},{"year":2012,"claim":"Mapping of the LRPPRC–COX1 mRNA interaction to the first 19 PPR motifs and a defined mRNA segment provided the first molecular-resolution view of how LRPPRC recognizes its mitochondrial substrates.","evidence":"Recombinant LRPPRC truncations in RNA-binding assays; gene-trap mouse with embryonic lethality and COX deficiency","pmids":["21880015"],"confidence":"High","gaps":["RNA recognition code for individual PPR motifs not decoded","Binding to non-COX1 transcripts not mapped at equivalent resolution"]},{"year":2013,"claim":"The earlier claim that LRPPRC activates mitochondrial transcription via POLRMT was refuted, firmly placing LRPPRC's function exclusively at the post-transcriptional level.","evidence":"BAC transgenic and heterozygous KO mice; in vitro transcription with purified LRPPRC; size-exclusion chromatography showing no POLRMT interaction","pmids":["23599432"],"confidence":"High","gaps":["Role in precursor RNA processing suggested but not mechanistically defined"]},{"year":2013,"claim":"Identification of the LRPPRC–Beclin 1–Bcl-2 ternary complex revealed a non-mitochondrial function: LRPPRC suppresses autophagy initiation by maintaining Bcl-2 stability and sequestering Beclin 1.","evidence":"Co-IP of ternary complex; LRPPRC knockdown with LC3-II, p62, and GFP-LC3 puncta readouts","pmids":["23822101"],"confidence":"Medium","gaps":["Single-lab finding; independent confirmation lacking","Whether this occurs at mitochondrial surface or elsewhere is ambiguous","Stoichiometry relative to primary mitochondrial RNA function unknown"]},{"year":2014,"claim":"Comprehensive OXPHOS phenotyping in LRPPRC-deficient hearts revealed that ATP synthase (complex V) assembly defects—not just COX deficiency—are a major consequence of LRPPRC loss, explaining hyperpolarization and ROS overproduction.","evidence":"Cardiac Lrpprc KO mice; OXPHOS complex activities, membrane potential, and ROS measurements","pmids":["24399447"],"confidence":"High","gaps":["Why ATP synthase is particularly sensitive to LRPPRC loss among OXPHOS complexes not explained"]},{"year":2014,"claim":"Analysis of LSFC patient tissues showed that the founder mutation reduces LRPPRC protein in a tissue-specific manner, explaining the tissue-selective pattern of combined complex I+IV deficiency in LSFC.","evidence":"LSFC patient-derived cell lines and tissues; BN-PAGE; OXPHOS complex activity measurements","pmids":["25214534"],"confidence":"High","gaps":["Molecular basis for tissue-specific LRPPRC protein stability not identified","Genotype-phenotype correlation for non-founder mutations incomplete"]},{"year":2015,"claim":"Slirp knockout mice dissected the division of labor within the LRPPRC–SLIRP complex: SLIRP is dispensable for polyadenylation but required for mRNA association with mitoribosomes, while LRPPRC is essential for both functions.","evidence":"Slirp KO mice; RNA-seq of mitoribosomal fractions; polyadenylation and translation assays","pmids":["26247782"],"confidence":"High","gaps":["How SLIRP facilitates ribosome association mechanistically was unknown"]},{"year":2016,"claim":"Structural and mutagenesis studies defined the LRPPRC–SLIRP heterodimer interface, showing that RNA-contacting residues in both proteins are repurposed for protein–protein interaction, explaining the obligate nature of the complex.","evidence":"In vitro reconstitution; mutagenesis of PPR motifs and RRM domain interface residues","pmids":["27353330"],"confidence":"High","gaps":["Full atomic-resolution structure of the heterodimer not determined at this point","How RNA binding is accommodated alongside the protein–protein interface unclear"]},{"year":2017,"claim":"Transcriptome-wide RNase footprinting and PAR-CLIP demonstrated that LRPPRC–SLIRP is a global RNA chaperone that reshapes the secondary structure of the entire mitochondrial transcriptome, exposing sites for translation, stabilization, and polyadenylation.","evidence":"Deep RNase footprinting combined with PAR-CLIP; LRPPRC loss-of-function analysis","pmids":["29146908"],"confidence":"High","gaps":["Whether chaperone activity is passive (binding-mediated unwinding) or active (ATP-dependent) not resolved","Structure-function relationship between individual PPR motifs and transcript regions not defined"]},{"year":2022,"claim":"Multiple studies identified LRPPRC as an m6A reader that stabilizes cytoplasmic mRNAs (MDR1, PD-L1, CDK6), establishing a post-transcriptional regulatory function for LRPPRC outside mitochondria that links it to chemoresistance, immune evasion, and cell cycle control.","evidence":"RIP and MeRIP-qPCR for m6A-dependent binding to MDR1 and PD-L1 mRNAs; mRNA stability assays; CDK6 mRNA RIP with ChIP showing reciprocal feedback loop","pmids":["35484333","37063837","37452037"],"confidence":"Medium","gaps":["m6A reading domain in LRPPRC not identified structurally","Selectivity among m6A-modified transcripts undefined","Findings from independent labs but each target studied by a single group"]},{"year":2022,"claim":"Influenza NS1 protein was shown to competitively displace Beclin 1 from LRPPRC, validating the LRPPRC–Beclin 1 axis as a physiologically targetable autophagy checkpoint exploited by pathogens.","evidence":"Co-IP and competitive binding assays; LRPPRC KO cell lines; autophagy markers during influenza infection","pmids":["36300799"],"confidence":"Medium","gaps":["Whether other viral proteins exploit the same interface unknown","In vivo relevance of this axis during infection not demonstrated"]},{"year":2024,"claim":"A cryo-EM structure of the LRPPRC–SLIRP–mRNA–mitoribosome complex revealed the physical mechanism of mRNA delivery: LRPPRC helical repeats contact mS39 and mS31 to form a corridor for mRNA handoff, and mitoribosome profiling confirmed transcript-specific effects on translation, particularly for COX1 and COX2.","evidence":"Cryo-EM structure determination; metabolic labeling; mitoribosome profiling","pmids":["39134711"],"confidence":"High","gaps":["How mRNA is released from LRPPRC into the decoding center not resolved","Whether LRPPRC remains associated during elongation or only during initiation unclear","Structural basis for transcript-specific translation effects not fully explained"]},{"year":null,"claim":"Key unresolved questions include the structural basis for LRPPRC's m6A-reading activity outside mitochondria, the mechanism by which LRPPRC partitions between mitochondrial and extra-mitochondrial pools, and how individual PPR motifs encode transcript selectivity within the mitochondrial transcriptome.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model for the m6A-binding interface","Dual-localization mechanism undetermined","PPR-RNA recognition code for mitochondrial transcript specificity not decoded"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,10,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,15,18]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,24,25]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,0,7,12,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,17,18]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,16,1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,24,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,15,18]}],"complexes":["LRPPRC-SLIRP heterodimer","PGC-1α coactivator complex","LRPPRC-Beclin 1-Bcl-2 complex"],"partners":["SLIRP","PGC1A","BECN1","BCL2","PRKN","MRPS39","MRPS31","CDK6"],"other_free_text":[]},"mechanistic_narrative":"LRPPRC is a pentatricopeptide repeat (PPR) protein that functions primarily in the mitochondrial matrix as a global post-transcriptional regulator of mitochondrial gene expression. In complex with SLIRP, it acts as an RNA chaperone that stabilizes mitochondrial mRNA secondary structures, promotes polyadenylation, maintains a pool of non-translated mRNAs, and physically delivers mRNAs to the mitoribosome via contacts with mS39 and mS31, with transcript-specific effects most pronounced on COX1 and COX2 [PMID:22045337, PMID:29146908, PMID:39134711]. Loss of LRPPRC causes combined OXPHOS deficiency—particularly complex IV and ATP synthase assembly defects—leading to impaired respiration, and biallelic mutations cause Leigh syndrome, French-Canadian type (LSFC), with tissue-specific patterns of OXPHOS dysfunction [PMID:24399447, PMID:25214534, PMID:28575497]. Outside mitochondria, LRPPRC participates in PGC-1α coactivator complexes to regulate gluconeogenic and thermogenic gene expression, suppresses autophagy by stabilizing a Bcl-2–Beclin 1 inhibitory complex, and functions as an m6A reader that stabilizes cytoplasmic mRNAs including MDR1, LDHA, and PD-L1 [PMID:17050673, PMID:23822101, PMID:35484333, PMID:37063837]."},"prefetch_data":{"uniprot":{"accession":"P42704","full_name":"Leucine-rich PPR motif-containing protein, mitochondrial","aliases":["130 kDa leucine-rich protein","LRP 130","GP130"],"length_aa":1394,"mass_kda":157.9,"function":"May play a role in RNA metabolism in both nuclei and mitochondria. In the nucleus binds to HNRPA1-associated poly(A) mRNAs and is part of nmRNP complexes at late stages of mRNA maturation which are possibly associated with nuclear mRNA export. Positively modulates nuclear export of mRNAs containing the EIF4E sensitivity element (4ESE) by binding simultaneously to both EIF4E and the 4ESE and acting as a platform for assembly for the RNA export complex (PubMed:19262567, PubMed:28325843). Also binds to exportin XPO1/CRM1 to engage the nuclear pore and traffic the bound mRNAs to the cytoplasm (PubMed:28325843). May bind mature mRNA in the nucleus outer membrane. In mitochondria binds to poly(A) mRNA. Plays a role in translation or stability of mitochondrially encoded cytochrome c oxidase (COX) subunits. May be involved in transcription regulation. Cooperates with PPARGC1A to regulate certain mitochondrially encoded genes and gluconeogenic genes and may regulate docking of PPARGC1A to transcription factors. Seems to be involved in the transcription regulation of the multidrug-related genes MDR1 and MVP. Part of a nuclear factor that binds to the invMED1 element of MDR1 and MVP gene promoters. Binds single-stranded DNA (By similarity). Required for maintaining mitochondrial potential (PubMed:23822101). 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gp130.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11412113","citation_count":27,"is_preprint":false},{"pmid":"25741592","id":"PMC_25741592","title":"Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model.","date":"2015","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25741592","citation_count":26,"is_preprint":false},{"pmid":"36328147","id":"PMC_36328147","title":"Deubiquitylase PSMD14 inhibits autophagy to promote ovarian cancer progression via stabilization of LRPPRC.","date":"2022","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/36328147","citation_count":24,"is_preprint":false},{"pmid":"26412102","id":"PMC_26412102","title":"The loss of LRPPRC function induces the mitochondrial unfolded protein response.","date":"2015","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/26412102","citation_count":24,"is_preprint":false},{"pmid":"32940862","id":"PMC_32940862","title":"Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERβ and IL-6/gp130/STAT3 signaling.","date":"2020","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/32940862","citation_count":23,"is_preprint":false},{"pmid":"35029286","id":"PMC_35029286","title":"Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer.","date":"2022","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35029286","citation_count":22,"is_preprint":false},{"pmid":"37496051","id":"PMC_37496051","title":"A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC-OXPHOS axis.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37496051","citation_count":22,"is_preprint":false},{"pmid":"31379810","id":"PMC_31379810","title":"Signaling Through gp130 Compromises Suppressive Function in Human FOXP3+ Regulatory T Cells.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31379810","citation_count":22,"is_preprint":false},{"pmid":"15786731","id":"PMC_15786731","title":"Protein phosphatase type 2A, PP2A, is involved in degradation of gp130.","date":"2005","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15786731","citation_count":22,"is_preprint":false},{"pmid":"38372449","id":"PMC_38372449","title":"LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m6 A modification in triple-negative breast cancer.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38372449","citation_count":21,"is_preprint":false},{"pmid":"33769697","id":"PMC_33769697","title":"E3 ubiquitin ligase NEDD4L negatively regulates keratinocyte hyperplasia by promoting GP130 degradation.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33769697","citation_count":21,"is_preprint":false},{"pmid":"24684823","id":"PMC_24684823","title":"Superantigen activates the gp130 receptor on adipocytes resulting in altered adipocyte metabolism.","date":"2014","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/24684823","citation_count":21,"is_preprint":false},{"pmid":"25228504","id":"PMC_25228504","title":"gp130 in late osteoblasts and osteocytes is required for PTH-induced osteoblast differentiation.","date":"2014","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25228504","citation_count":21,"is_preprint":false},{"pmid":"37058568","id":"PMC_37058568","title":"IL-6-GP130 signaling protects human hepatocytes against lipid droplet accumulation in humanized liver models.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37058568","citation_count":21,"is_preprint":false},{"pmid":"32149459","id":"PMC_32149459","title":"LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1α-FOXO4-p21-dependent signaling axis.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/32149459","citation_count":20,"is_preprint":false},{"pmid":"22808186","id":"PMC_22808186","title":"Knockdown of the cellular protein LRPPRC attenuates HIV-1 infection.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22808186","citation_count":20,"is_preprint":false},{"pmid":"31391340","id":"PMC_31391340","title":"Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31391340","citation_count":20,"is_preprint":false},{"pmid":"36300799","id":"PMC_36300799","title":"A/(H1N1) pdm09 NS1 promotes viral replication by enhancing autophagy through hijacking the IAV negative regulatory factor LRPPRC.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/36300799","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47959,"output_tokens":6162,"usd":0.118153},"stage2":{"model":"claude-opus-4-6","input_tokens":9890,"output_tokens":3813,"usd":0.217163},"total_usd":0.335316,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"LRPPRC forms an RNA-dependent protein complex necessary for maintaining a pool of non-translated mitochondrial mRNAs; loss of LRPPRC decreases mRNA stability, abolishes mRNA polyadenylation, and causes aberrant (misregulated) mitochondrial translation, including excessive translation of some transcripts and no translation of others.\",\n      \"method\": \"Conditional Lrpprc knockout mice (heart-specific); steady-state mRNA analysis, polyadenylation assays, mitochondrial translation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo conditional KO with multiple orthogonal molecular readouts (mRNA stability, polyadenylation, translation profiling)\",\n      \"pmids\": [\"22045337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LRP130 (LRPPRC) is a component of the PGC-1α transcriptional coactivator holocomplex in the nucleus and regulates expression of gluconeogenic genes (PEPCK, G6P) and certain mitochondrial genes through PGC-1α; adenoviral RNAi knockdown of LRP130 in fasted mice blocks induction of PEPCK and G6P and blunts hepatic glucose output.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry of PGC-1α complex; adenoviral RNAi knockdown in mice; gene expression analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying complex + in vivo KD with defined metabolic phenotype\",\n      \"pmids\": [\"17050673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LRPPRC is exclusively localized to the mitochondrial matrix in mammalian cells; it is imported into the matrix with cleavage of its mitochondrial targeting sequence upon entry, and orthologous proteins in metazoans all contain mitochondrial targeting signals.\",\n      \"method\": \"Subcellular fractionation, bioinformatic analysis of mitochondrial targeting signals, direct localization experiments in mammalian cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation experiment with functional localization determination, supported by bioinformatics\",\n      \"pmids\": [\"20633537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNAi-mediated knockdown of LRPPRC specifically reduces steady-state levels of all mitochondrial DNA-encoded mRNAs but not mitochondrial rRNAs, establishing a specific role for LRPPRC in mtDNA-encoded mRNA expression.\",\n      \"method\": \"Stable RNAi knockdown allelic series in cells; genome-wide expression profiling with gene set enrichment analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic perturbation with multiple knockdown levels and genome-wide readout\",\n      \"pmids\": [\"20220140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The LRPPRC–SLIRP complex functions as a global RNA chaperone that stabilizes RNA secondary structures throughout the mitochondrial transcriptome (preferentially mRNAs), exposing sites required for translation, stabilization, and polyadenylation; loss of LRPPRC affects the entire secondary structure and stability of the mitochondrial transcriptome.\",\n      \"method\": \"RNase footprinting combined with PAR-CLIP at high depth; loss-of-function analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — deep RNase footprinting + PAR-CLIP providing transcriptome-wide structural data, replicated in loss-of-function context\",\n      \"pmids\": [\"29146908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLIRP stabilizes LRPPRC by protecting it from degradation; SLIRP is completely dependent on LRPPRC for its own stability; SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs but is required for proper association of mRNAs with the mitochondrial ribosome and efficient translation.\",\n      \"method\": \"Slirp knockout mice; RNA sequencing of mitochondrial ribosomal fractions; molecular analyses of mRNA polyadenylation and translation\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo KO mice with multiple molecular readouts distinguishing SLIRP vs. LRPPRC functions\",\n      \"pmids\": [\"26247782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LRPPRC and SLIRP form a stable heterodimer via interactions between three neighbouring PPR motifs in the second quarter of LRPPRC and the single RRM domain of SLIRP; residues predicted to contact RNA in both proteins are instead used for protein–protein interactions at the binding interface.\",\n      \"method\": \"In vitro RNA binding assays; mutagenesis of interface residues; biochemical characterization of the heterodimer\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis defining molecular interface\",\n      \"pmids\": [\"27353330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of LRPPRC in conditional knockout mouse hearts causes impaired mitochondrial respiration and reduced ATP production primarily through an ATP synthase (complex V) deficiency, not only COX deficiency; inactive subassembled ATP synthase complexes cause mitochondrial hyperpolarization and increased ROS production.\",\n      \"method\": \"Conditional Lrpprc cardiac knockout mice; measurement of respiratory chain complex activities, ATP production, mitochondrial membrane potential, ROS\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple biochemical readouts revealing unexpected pathway (ATP synthase vs. COX)\",\n      \"pmids\": [\"24399447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LRP130 (LRPPRC) complexes with the mitochondrial RNA polymerase (POLRMT) to activate mitochondrial transcription, which is associated with increased OXPHOS activity, increased respiratory supercomplexes, denser cristae, and elevated ATP; LRP130 also increases hepatic β-fatty acid oxidation.\",\n      \"method\": \"Genetic and biochemical approaches; co-immunoprecipitation of LRP130 with POLRMT; measurement of OXPHOS activity, ATP, supercomplexes, fatty acid oxidation using 14C-palmitate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional metabolic assays in single study; partially contradicted by later work (PMID 23599432)\",\n      \"pmids\": [\"21971050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LRPPRC does not directly interact with POLRMT or activate mtDNA transcription; variation in LRPPRC levels in vivo affects unprocessed mitochondrial precursor transcripts but not steady-state transcript levels or de novo transcription; LRPPRC acts exclusively as a post-transcriptional regulator.\",\n      \"method\": \"BAC transgenic mice with increased LRPPRC; heterozygous Lrpprc KO mice; size exclusion chromatography; co-immunoprecipitation; in vitro transcription system with purified LRPPRC\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution assay, in vivo genetic models, and Co-IP all converge on same conclusion\",\n      \"pmids\": [\"23599432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRPPRC binds directly to a specific segment of COX1 mRNA (mouse mtDNA nucleotides 5961–6020) via its first 19 PPR motifs, and this binding stabilizes mitochondrial mRNA transcripts encoding COX subunits; homozygous LRPPRC disruption causes embryonic lethality and major COX activity decrease in MEFs.\",\n      \"method\": \"Gene-trap mouse model; RNA binding assays with recombinant LRPPRC truncation constructs containing different numbers of PPR motifs; biochemical measurement of respiratory chain complex activities\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro RNA binding reconstitution with deletion mapping + in vivo mouse model\",\n      \"pmids\": [\"21880015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRPPRC forms a ribonucleoprotein complex with SLIRP that stabilizes polyadenylated mitochondrial mRNAs; LSFC founder mutation reduces LRPPRC levels in a tissue-specific manner, leading to tissue-specific patterns of OXPHOS deficiency (combined complex I+IV in muscle, severe complex IV loss in liver).\",\n      \"method\": \"Analysis of LSFC patient-derived cell lines and tissues; BN-PAGE; measurement of OXPHOS complex activities; LRPPRC/SLIRP levels by western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple patient tissues with orthogonal biochemical methods\",\n      \"pmids\": [\"25214534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRPPRC functions as an mRNA delivery factor that recruits mitochondrial mRNAs to the mitoribosome; cryo-EM structure of the LRPPRC–SLIRP–mRNA–mitoribosome complex shows LRPPRC associates with mitoribosomal proteins mS39 and the N-terminus of mS31 through its helical repeats, forming a corridor for mRNA handoff; SLIRP directly binds mRNA and stabilizes LRPPRC; LRPPRC-SLIRP has transcript-specific influence on mRNA translation efficiency, with COX1 and COX2 translation most affected.\",\n      \"method\": \"Cryo-electron microscopy structure determination; RNA sequencing; metabolic labeling; mitoribosome profiling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with functional validation by metabolic labeling and ribosome profiling\",\n      \"pmids\": [\"39134711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LRPPRC associates with mitochondria, interacts with Beclin 1 and Bcl-2, and forms a ternary complex to maintain Bcl-2 stability; suppression of LRPPRC reduces mitochondrial potential and Bcl-2 levels, releasing Beclin 1 to form the Beclin1–PI3KCIII complex and activating autophagy upstream of ATG5-ATG12-mediated LC3-I to LC3-II conversion.\",\n      \"method\": \"Co-immunoprecipitation of LRPPRC–Beclin1–Bcl-2 complex; LRPPRC knockdown in multiple cell lines; autophagy markers (GFP-LC3 puncta, LC3-II, p62); PI3K/Akt/mTOR pathway analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifying ternary complex + multiple cellular autophagy readouts, single lab\",\n      \"pmids\": [\"23822101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRPPRC maintains the stability of Parkin (which mono-ubiquitinates Bcl-2 to increase Bcl-2 stability and inhibit autophagy); under mitophagy stress, Parkin translocates to mitochondria, binds exposed LRPPRC on ruptured outer mitochondrial membrane, and LRPPRC together with Parkin promotes engulfment of mitochondria into autophagosomes.\",\n      \"method\": \"Co-immunoprecipitation of LRPPRC–Parkin; mitophagy stress assays; immunofluorescence of Parkin translocation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus live-cell imaging, single lab\",\n      \"pmids\": [\"24722279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LRP130 is a component of PGC-1α coactivator complexes in brown adipocytes; LRP130 is preferentially enriched in brown versus white fat and is induced in a PGC-1-dependent manner during differentiation; brown fat cells deficient for LRP130 show attenuated expression of UCP1 and reduced proton leak.\",\n      \"method\": \"ShRNA knockdown of LRP130 in brown adipocytes; oxygen consumption assays; gene expression analysis; PGC-1α coactivator complex binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — KD with metabolic phenotype + PGC-1α complex association, single lab\",\n      \"pmids\": [\"18728005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of hepatic LRPPRC causes severe complex IV and ATP synthase assembly defects, impairs long-chain fatty acid oxidation, dysregulates the mitochondrial permeability transition pore, and alters trans-membrane H2O2 diffusion; the H2O2 alteration is traced to ATP synthase assembly defect and changes in mitochondrial membrane lipid composition.\",\n      \"method\": \"Hepatocyte-specific Lrpprc knockout mice; mitochondrial phenotyping including OXPHOS complex activities, ultrastructure, fatty acid oxidation, permeability transition pore assays, ROS measurements\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo KO with comprehensive mitochondrial phenotyping across multiple orthogonal assays\",\n      \"pmids\": [\"28575497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LRP130 (LRPPRC) binds to the invMED1 cis-activating element in the promoters of MDR1 and MVP genes in the nucleus and is involved in transcriptional activation of these multidrug resistance-related genes; its binding intensity increases with MDR1 expression.\",\n      \"method\": \"Electrophoretic mobility shift assay; siRNA knockdown; transcriptional decoy experiments; nuclear factor identification\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — DNA binding assay + siRNA with functional gene expression readout, single lab\",\n      \"pmids\": [\"15272088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRPPRC forms a transcriptional repressor complex with PGC1α on the FOXO4 promoter; lncRNA GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promoter, thereby suppressing FOXO4 and p21 expression and preventing cellular senescence.\",\n      \"method\": \"Co-immunoprecipitation of LRP130–PGC1α complex; ChIP at FOXO4 promoter; siRNA knockdown of LRP130/PGC1α; senescence assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP + ChIP + functional senescence readout, single lab\",\n      \"pmids\": [\"32149459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRPPRC binds to CDK6 mRNA, increasing its stability and protein expression; CDK6 and its downstream effector E2F1 bind to the LRPPRC promoter and elevate LRPPRC transcription, forming a positive feedback LRPPRC–CDK6 loop that promotes G1/S transition, oxidative phosphorylation, and cancer stem cell generation.\",\n      \"method\": \"RNA immunoprecipitation (RIP) showing LRPPRC–CDK6 mRNA binding; mRNA stability assays; ChIP showing CDK6/E2F1 at LRPPRC promoter; functional cell cycle, OXPHOS, and stem cell assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — RIP, mRNA stability assay, ChIP, and functional rescue experiments in single study\",\n      \"pmids\": [\"37452037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LRPPRC acts as an m6A reader that binds the m6A modification site of MDR1 mRNA and enhances MDR1 mRNA stability and protein expression; P53 normally suppresses LRPPRC via miR-34a; when P53 is mutated, LRPPRC and MDR1 accumulate, promoting chemoresistance.\",\n      \"method\": \"RIP assays; RNA stability assays; miR-34a/LRPPRC/MDR1 pathway analysis; in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP demonstrating m6A-dependent mRNA binding + functional pathway validation, single lab\",\n      \"pmids\": [\"35484333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRPPRC functions as an m6A reader that posttranscriptionally upregulates PD-L1 mRNA stability in an m6A-dependent manner in hepatocellular carcinoma, promoting immune evasion.\",\n      \"method\": \"RIP, MeRIP-qPCR, RNA stability assays, xenograft tumor models, immunohistochemical staining\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple RNA biochemistry methods demonstrating m6A reading function, single lab\",\n      \"pmids\": [\"37063837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRPPRC promotes glycolysis in triple-negative breast cancer by recognizing the m6A site of LDHA mRNA and enhancing LDHA mRNA stability; LRPPRC knockdown reduces glycolysis while glutaminolysis is enhanced, creating synthetic lethality when combined with glutaminase inhibition.\",\n      \"method\": \"MeRIP-sequencing, RNA-immunoprecipitation, RNA pull-down, RNA stability assays, Seahorse metabolic assays, patient-derived xenografts and organoids\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — MeRIP-seq + multiple RNA biochemistry methods identifying LDHA as direct m6A target, single lab\",\n      \"pmids\": [\"38372449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRPPRC associates with HIV-1 nucleic acids during early infection (co-immunoprecipitation RT-PCR); knockdown of LRPPRC reduces preintegration complex formation and viral DNA nuclear import, identifying LRPPRC as a host factor required for early steps of HIV-1 replication.\",\n      \"method\": \"Co-immunoprecipitation RT-PCR; stable LRPPRC knockdown cell lines; subcellular fractionation; viral replication assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP demonstrating LRPPRC–viral nucleic acid association + KD with defined replication defects, single lab\",\n      \"pmids\": [\"22808186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Influenza A (H1N1)pdm09 NS1 protein directly interacts with LRPPRC and competitively blocks the interaction of LRPPRC with BECN1, thereby releasing BECN1 to activate PIK3C3 and induce autophagy initiation, promoting viral replication.\",\n      \"method\": \"Co-immunoprecipitation; competitive binding assays; LRPPRC knockout cell lines; autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP demonstrating competitive displacement of BECN1 from LRPPRC + KO validation, single lab\",\n      \"pmids\": [\"36300799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMD14 deubiquitinase directly interacts with LRPPRC and inhibits its ubiquitination, thereby stabilizing LRPPRC protein; stabilized LRPPRC in turn suppresses autophagy through the LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation of PSMD14–LRPPRC; ubiquitination assays; autophagy marker analysis; in vivo xenograft models\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifying deubiquitinase–substrate interaction + functional autophagy readout, single lab\",\n      \"pmids\": [\"36328147\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRPPRC is a mitochondrial matrix PPR-protein that, in complex with SLIRP, functions as a global RNA chaperone and mRNA delivery factor: it stabilizes mitochondrial mRNA secondary structures, promotes their polyadenylation, maintains a pool of non-translated mRNAs, and physically recruits mRNAs to the mitoribosome (via contacts with mS39/mS31) for translation, with transcript-specific effects particularly on COX1/COX2; outside mitochondria, LRPPRC can act in the nucleus as part of PGC-1α coactivator complexes to regulate gluconeogenic and brown-fat genes, and functions as an m6A reader to stabilize cytoplasmic mRNAs (including MDR1, LDHA, PD-L1), while also suppressing autophagy initiation by maintaining a Bcl-2–Beclin1 inhibitory complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRPPRC is a pentatricopeptide repeat (PPR) protein that functions primarily in the mitochondrial matrix as a global post-transcriptional regulator of mitochondrial gene expression. In complex with SLIRP, it acts as an RNA chaperone that stabilizes mitochondrial mRNA secondary structures, promotes polyadenylation, maintains a pool of non-translated mRNAs, and physically delivers mRNAs to the mitoribosome via contacts with mS39 and mS31, with transcript-specific effects most pronounced on COX1 and COX2 [PMID:22045337, PMID:29146908, PMID:39134711]. Loss of LRPPRC causes combined OXPHOS deficiency—particularly complex IV and ATP synthase assembly defects—leading to impaired respiration, and biallelic mutations cause Leigh syndrome, French-Canadian type (LSFC), with tissue-specific patterns of OXPHOS dysfunction [PMID:24399447, PMID:25214534, PMID:28575497]. Outside mitochondria, LRPPRC participates in PGC-1α coactivator complexes to regulate gluconeogenic and thermogenic gene expression, suppresses autophagy by stabilizing a Bcl-2–Beclin 1 inhibitory complex, and functions as an m6A reader that stabilizes cytoplasmic mRNAs including MDR1, LDHA, and PD-L1 [PMID:17050673, PMID:23822101, PMID:35484333, PMID:37063837].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"The initial identification of LRPPRC as a nuclear DNA-binding factor at the MDR1 promoter raised the question of whether it functions in gene regulation beyond mitochondria.\",\n      \"evidence\": \"EMSA and siRNA knockdown linking LRP130 to invMED1-dependent transcriptional activation of MDR1/MVP\",\n      \"pmids\": [\"15272088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear DNA-binding function not independently replicated\", \"Relationship to predominant mitochondrial localization unresolved\", \"No structural basis for DNA recognition\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that LRPPRC is a stable component of the PGC-1α transcriptional coactivator complex established its role in nuclear transcriptional regulation of gluconeogenic and mitochondrial genes, answering how hepatic glucose output is coordinated with mitochondrial biogenesis.\",\n      \"evidence\": \"Co-IP/mass spectrometry of PGC-1α complex; adenoviral RNAi in fasted mice showing blunted PEPCK/G6P induction\",\n      \"pmids\": [\"17050673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which LRPPRC partitions between nucleus and mitochondria unknown\", \"Direct vs. indirect effect on PGC-1α target promoters not distinguished\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Definitive localization of LRPPRC to the mitochondrial matrix and demonstration that its loss selectively reduces all mtDNA-encoded mRNAs (but not rRNAs) resolved the primary site of action and established transcript-class specificity.\",\n      \"evidence\": \"Subcellular fractionation and MTS cleavage analysis; RNAi allelic series with genome-wide expression profiling\",\n      \"pmids\": [\"20633537\", \"20220140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mRNA selectivity over rRNA unknown\", \"Whether a dual nuclear-mitochondrial pool exists in vivo remained debated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Conditional knockout in mouse hearts revealed that LRPPRC maintains a pool of non-translated polyadenylated mRNAs and that its loss abolishes polyadenylation while causing globally dysregulated mitochondrial translation, establishing LRPPRC as a post-transcriptional coordinator rather than simply a stabilizer.\",\n      \"evidence\": \"Heart-specific Lrpprc KO mice; mRNA polyadenylation assays and metabolic labeling of mitochondrial translation\",\n      \"pmids\": [\"22045337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LRPPRC coordinates polyadenylation machinery mechanistically unclear\", \"Transcript-specific translation effects not fully explained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping of the LRPPRC–COX1 mRNA interaction to the first 19 PPR motifs and a defined mRNA segment provided the first molecular-resolution view of how LRPPRC recognizes its mitochondrial substrates.\",\n      \"evidence\": \"Recombinant LRPPRC truncations in RNA-binding assays; gene-trap mouse with embryonic lethality and COX deficiency\",\n      \"pmids\": [\"21880015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA recognition code for individual PPR motifs not decoded\", \"Binding to non-COX1 transcripts not mapped at equivalent resolution\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The earlier claim that LRPPRC activates mitochondrial transcription via POLRMT was refuted, firmly placing LRPPRC's function exclusively at the post-transcriptional level.\",\n      \"evidence\": \"BAC transgenic and heterozygous KO mice; in vitro transcription with purified LRPPRC; size-exclusion chromatography showing no POLRMT interaction\",\n      \"pmids\": [\"23599432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role in precursor RNA processing suggested but not mechanistically defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of the LRPPRC–Beclin 1–Bcl-2 ternary complex revealed a non-mitochondrial function: LRPPRC suppresses autophagy initiation by maintaining Bcl-2 stability and sequestering Beclin 1.\",\n      \"evidence\": \"Co-IP of ternary complex; LRPPRC knockdown with LC3-II, p62, and GFP-LC3 puncta readouts\",\n      \"pmids\": [\"23822101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent confirmation lacking\", \"Whether this occurs at mitochondrial surface or elsewhere is ambiguous\", \"Stoichiometry relative to primary mitochondrial RNA function unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Comprehensive OXPHOS phenotyping in LRPPRC-deficient hearts revealed that ATP synthase (complex V) assembly defects—not just COX deficiency—are a major consequence of LRPPRC loss, explaining hyperpolarization and ROS overproduction.\",\n      \"evidence\": \"Cardiac Lrpprc KO mice; OXPHOS complex activities, membrane potential, and ROS measurements\",\n      \"pmids\": [\"24399447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why ATP synthase is particularly sensitive to LRPPRC loss among OXPHOS complexes not explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Analysis of LSFC patient tissues showed that the founder mutation reduces LRPPRC protein in a tissue-specific manner, explaining the tissue-selective pattern of combined complex I+IV deficiency in LSFC.\",\n      \"evidence\": \"LSFC patient-derived cell lines and tissues; BN-PAGE; OXPHOS complex activity measurements\",\n      \"pmids\": [\"25214534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for tissue-specific LRPPRC protein stability not identified\", \"Genotype-phenotype correlation for non-founder mutations incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Slirp knockout mice dissected the division of labor within the LRPPRC–SLIRP complex: SLIRP is dispensable for polyadenylation but required for mRNA association with mitoribosomes, while LRPPRC is essential for both functions.\",\n      \"evidence\": \"Slirp KO mice; RNA-seq of mitoribosomal fractions; polyadenylation and translation assays\",\n      \"pmids\": [\"26247782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLIRP facilitates ribosome association mechanistically was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structural and mutagenesis studies defined the LRPPRC–SLIRP heterodimer interface, showing that RNA-contacting residues in both proteins are repurposed for protein–protein interaction, explaining the obligate nature of the complex.\",\n      \"evidence\": \"In vitro reconstitution; mutagenesis of PPR motifs and RRM domain interface residues\",\n      \"pmids\": [\"27353330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic-resolution structure of the heterodimer not determined at this point\", \"How RNA binding is accommodated alongside the protein–protein interface unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Transcriptome-wide RNase footprinting and PAR-CLIP demonstrated that LRPPRC–SLIRP is a global RNA chaperone that reshapes the secondary structure of the entire mitochondrial transcriptome, exposing sites for translation, stabilization, and polyadenylation.\",\n      \"evidence\": \"Deep RNase footprinting combined with PAR-CLIP; LRPPRC loss-of-function analysis\",\n      \"pmids\": [\"29146908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chaperone activity is passive (binding-mediated unwinding) or active (ATP-dependent) not resolved\", \"Structure-function relationship between individual PPR motifs and transcript regions not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple studies identified LRPPRC as an m6A reader that stabilizes cytoplasmic mRNAs (MDR1, PD-L1, CDK6), establishing a post-transcriptional regulatory function for LRPPRC outside mitochondria that links it to chemoresistance, immune evasion, and cell cycle control.\",\n      \"evidence\": \"RIP and MeRIP-qPCR for m6A-dependent binding to MDR1 and PD-L1 mRNAs; mRNA stability assays; CDK6 mRNA RIP with ChIP showing reciprocal feedback loop\",\n      \"pmids\": [\"35484333\", \"37063837\", \"37452037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reading domain in LRPPRC not identified structurally\", \"Selectivity among m6A-modified transcripts undefined\", \"Findings from independent labs but each target studied by a single group\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Influenza NS1 protein was shown to competitively displace Beclin 1 from LRPPRC, validating the LRPPRC–Beclin 1 axis as a physiologically targetable autophagy checkpoint exploited by pathogens.\",\n      \"evidence\": \"Co-IP and competitive binding assays; LRPPRC KO cell lines; autophagy markers during influenza infection\",\n      \"pmids\": [\"36300799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether other viral proteins exploit the same interface unknown\", \"In vivo relevance of this axis during infection not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A cryo-EM structure of the LRPPRC–SLIRP–mRNA–mitoribosome complex revealed the physical mechanism of mRNA delivery: LRPPRC helical repeats contact mS39 and mS31 to form a corridor for mRNA handoff, and mitoribosome profiling confirmed transcript-specific effects on translation, particularly for COX1 and COX2.\",\n      \"evidence\": \"Cryo-EM structure determination; metabolic labeling; mitoribosome profiling\",\n      \"pmids\": [\"39134711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mRNA is released from LRPPRC into the decoding center not resolved\", \"Whether LRPPRC remains associated during elongation or only during initiation unclear\", \"Structural basis for transcript-specific translation effects not fully explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for LRPPRC's m6A-reading activity outside mitochondria, the mechanism by which LRPPRC partitions between mitochondrial and extra-mitochondrial pools, and how individual PPR motifs encode transcript selectivity within the mitochondrial transcriptome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model for the m6A-binding interface\", \"Dual-localization mechanism undetermined\", \"PPR-RNA recognition code for mitochondrial transcript specificity not decoded\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 10, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 15, 18]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 24, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 0, 7, 12, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 17, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 16, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 24, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 15, 18]}\n    ],\n    \"complexes\": [\n      \"LRPPRC-SLIRP heterodimer\",\n      \"PGC-1α coactivator complex\",\n      \"LRPPRC-Beclin 1-Bcl-2 complex\"\n    ],\n    \"partners\": [\n      \"SLIRP\",\n      \"PGC1A\",\n      \"BECN1\",\n      \"BCL2\",\n      \"PRKN\",\n      \"MRPS39\",\n      \"MRPS31\",\n      \"CDK6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}