{"gene":"PISD","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2005,"finding":"PISD (phosphatidylserine decarboxylase) is essential for mitochondrial morphology and embryonic development; knockout mice die between embryonic days 8–10 with fragmented, misshapen mitochondria, demonstrating that mitochondrial PE synthesis via PS decarboxylation is required for normal mitochondrial structure and cannot be compensated by the CDP-ethanolamine pathway during development.","method":"Knockout mouse generation, electron microscopy, fluorescence confocal microscopy, radiolabeled PE synthesis assays, immunoblotting of compensatory pathway enzymes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — genetic KO with multiple orthogonal readouts (EM, confocal, biochemical assays), highly cited foundational study","pmids":["16192276"],"is_preprint":false},{"year":2018,"finding":"PISD activity and mitochondrial-associated membrane (MAM) contacts are required for maximal autophagy induction downstream of mTOR inhibition; complex I dysfunction suppresses autophagy by preventing the increase in MAMs and limiting PISD-dependent mitochondrial PE (mtPE) production needed to support autophagosome biogenesis.","method":"Genetic defects in complex I, phenformin treatment, mTOR inhibitor treatment, phospholipid mass spectrometry, MAM quantification, autophagy flux assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods linking PISD activity to MAM contacts and autophagy, with pharmacological and genetic perturbations","pmids":["30157433"],"is_preprint":false},{"year":2018,"finding":"The missense variant p.(Cys266Tyr) in PISD causes impaired phosphatidylserine decarboxylase function, leading to fragmented mitochondrial morphology in patient fibroblasts and increased apoptotic sensitivity; ethanolamine supplementation restores cell viability, confirming the causal role of reduced PE synthesis.","method":"Trio-exome sequencing, patient-derived fibroblast analysis, mitochondrial morphology imaging, caspase-3/7 activation assays, ethanolamine rescue","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — patient fibroblast functional validation with multiple readouts, single study","pmids":["30488656"],"is_preprint":false},{"year":2019,"finding":"Compound heterozygous PISD variants cause impaired PS-to-PE conversion in the inner mitochondrial membrane (IMM); one paternal variant impairs autocatalytic self-processing of the PISD precursor required for enzymatic activity, while the maternal variant causes aberrant splicing; lyso-PE supplementation or genetic complementation restores mitochondrial and lysosome morphology.","method":"Exome sequencing, PS-to-PE conversion assays in patient fibroblasts, mitochondrial morphology imaging, oxygen consumption rate measurement, lyso-PE rescue, genetic complementation, splice product analysis","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic activity directly measured, autocatalytic processing mechanism identified, multiple orthogonal rescue experiments","pmids":["30858161"],"is_preprint":false},{"year":2019,"finding":"A founder 10-bp deletion in PISD immediately upstream of the last exon causes aberrant splicing of PISD transcripts in HEK293T cells, establishing loss of functional PISD as the genetic basis of Liberfarb syndrome (retinal degeneration, sensorineural hearing loss, microcephaly, skeletal dysplasia).","method":"Exome sequencing, autozygosity mapping, minigene construct splicing assay in HEK293T cells, qPCR, Sanger sequencing of paraffin-embedded tissue","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 — splicing mechanism validated in cell-based minigene assay, single study","pmids":["31263216"],"is_preprint":false},{"year":2018,"finding":"PISD overexpression reduces tumor-initiating potential of breast cancer cells in mammosphere assays and mouse xenograft models and regulates multiple aspects of mitochondrial function; PISD is downregulated ~8-fold in migratory/tumor-initiating cells.","method":"Microfluidic migration isolation, whole-transcriptome sequencing, PISD overexpression, mammosphere assay, mouse xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss/gain of function with defined cellular phenotype, single lab","pmids":["29321615"],"is_preprint":false},{"year":2021,"finding":"PISD localizes to the inner mitochondrial membrane and to lipid droplets via an alternatively spliced isoform (PISD-LD); sub-cellular targeting is controlled by a segment distinct from the catalytic domain and is regulated by nutritional state (lipid storage conditions favor lipid droplet targeting, lipid consumption favors mitochondrial targeting); depletion of both forms impairs triacylglycerol synthesis during fatty acid challenge.","method":"Alternative splice variant characterization, sub-cellular fractionation, fluorescence localization, nutritional perturbation, siRNA depletion, triacylglycerol synthesis assay","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments with functional consequence, multiple conditions tested","pmids":["33593792"],"is_preprint":false},{"year":2020,"finding":"TFAM knockdown reduces PISD expression through a mechanism involving increased NAD+/NADH ratio, upregulation of SIRT1, deacetylation of p53 at lysine 382, and reduced p53 transcriptional activation of the PISD enhancer; decreased PISD then reduces LC3-II levels and impairs autophagy.","method":"TFAM siRNA knockdown, PISD siRNA knockdown, LC3-II immunoblot, NAD+/NADH measurement, SIRT1 activity assay, p53 acetylation analysis, luciferase/ChIP-based transcription assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established through multiple biochemical measurements in single lab","pmids":["32093281"],"is_preprint":false},{"year":2021,"finding":"TGF-β1-induced myofibroblast transition reduces PISD expression in mitochondria; PISD knockdown alone (without TGF-β1) is sufficient to increase α-smooth muscle actin mRNA and collagen production, placing PISD activity upstream of fibrogenesis through phospholipid metabolism.","method":"TGF-β1 stimulation, lipidomic analysis, PISD siRNA knockdown, α-SMA mRNA quantification, collagen production assay","journal":"Journal of clinical biochemistry and nutrition","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular phenotype and pathway placement, single lab","pmids":["35400823"],"is_preprint":false},{"year":2002,"finding":"Brain mitochondrial PISD (phosphatidylserine decarboxylase) activity shows tissue-dependent and age-dependent substrate preferences based on DHA (22:6n-3) content of the phosphatidylserine substrate; cerebellar PISD activity is specifically inhibited during aging.","method":"Mitochondrial fraction isolation from rat cerebral cortex and cerebellum, enzymatic activity assays with PS substrates of defined fatty acid composition","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic activity assays with defined substrates, single lab","pmids":["12391587"],"is_preprint":false},{"year":2023,"finding":"PISD downregulation by high uric acid (via inhibited STAT3 phosphorylation) reduces mitochondrial PE levels and impairs mitochondrial respiration, inducing apoptosis; PISD overexpression or lyso-PE supplementation rescues these effects in vitro.","method":"Lipidomic analysis of mitochondria, PISD overexpression, lyso-PE supplementation, STAT3 phosphorylation assays, mitochondrial respiration measurement, apoptosis assays","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal rescue approaches, single lab","pmids":["37502610"],"is_preprint":false},{"year":2024,"finding":"SLMO (the Drosophila ortholog of SLMO2) specifically transfers phosphatidylserine from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) within the inner boundary membrane domain, providing substrate for PISD to synthesize PE; genetic evidence places PSS→SLMO→PISD in a conserved pathway required for mitochondrial morphology.","method":"Forward genetic screen in Drosophila, epistasis analysis of PSS-SLMO-PISD pathway, mitochondrial morphology assays, SLMO2 human complementation","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 — genetic epistasis with forward screen, pathway reconstituted in vivo, conservation validated in human cells","pmids":["39680501"],"is_preprint":false},{"year":2024,"finding":"Novel compound heterozygous PISD missense variants p.(Ser190Leu) and p.(His267Tyr) likely impair PISD autocatalytic self-processing and/or PE biosynthesis based on structural homology to E. coli ortholog; patient fibroblasts show significantly higher mitochondrial fragmentation compared to controls.","method":"Trio genome sequencing, fibroblast mitochondrial morphology imaging with 2-deoxyglucose stress, structural modeling using E. coli PISD ortholog crystal data","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional fibroblast data combined with structural modeling, single study","pmids":["38801004"],"is_preprint":false},{"year":2025,"finding":"PISD deficiency in HEPA1-6 hepatocellular carcinoma cells impairs mitochondrial fatty acid and glucose oxidation, reduces electron transport chain complex I and IV abundance, increases mitochondrial superoxide, augments mitochondrial fission and mitophagy, and reduces cell proliferation via reduced mTOR signaling; peroxisomal fat oxidation and anaerobic glycolysis partially compensate.","method":"PISD siRNA silencing, mitochondrial respiration assays (Seahorse), ETC complex abundance (immunoblot), mitochondrial dynamics imaging, cell proliferation assays, mTOR signaling assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal phenotypic readouts from single lab KD experiment","pmids":["41360863"],"is_preprint":false},{"year":2025,"finding":"PISD depletion in gastric cancer cells reduces PE levels, decreases STAT3 phosphorylation and GPX4 expression, increases lipid peroxidation and iron accumulation, enhancing ferroptosis; Ferrostatin-1, STAT3 activator ML115, or lyso-PE supplementation partially rescues PISD knockdown-induced ferroptosis, defining a PISD→STAT3→GPX4 axis.","method":"PISD knockdown, PE quantification, STAT3 phosphorylation immunoblot, GPX4 immunoblot, lipid peroxidation assays, ferroptosis rescue with Fer-1/ML115/LPE, xenograft tumor growth","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway established with pharmacological rescues, single lab","pmids":["41899452"],"is_preprint":false},{"year":2025,"finding":"PISD overexpression directly upregulates SPG7 (a critical mPTP component) expression, inhibits mitochondrial permeability transition pore opening, and reverses necroptosis induced by nano-zinc oxide in inflammatory HaCaT cells, establishing a PISD→SPG7→mPTP axis.","method":"PISD overexpression, SPG7 overexpression, mPTP opening assay, p-MLKL immunoblot, mitochondrial morphology imaging","journal":"Toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with mechanistic pathway placement, single lab","pmids":["40780696"],"is_preprint":false},{"year":2025,"finding":"Reduction in ER-mitochondria contacts in aged cardiomyocytes impairs PS lipid transport to mitochondria; combined with PISD deficiency, this reduces PE production, impairing autophagosomal membrane formation and autophagic flux, leading to accumulation of dysfunctional giant mitochondria; modulating LACTB expression to enhance PISD activity restores mitochondrial homeostasis.","method":"Aged mouse models, etoposide-induced senescence, ER-Mito contact quantification, PE measurement, autophagy flux assays, LACTB manipulation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — multiple models and mechanistic interventions, single lab","pmids":["40254645"],"is_preprint":false},{"year":2017,"finding":"Hepatic CDS2 deficiency impairs mitochondrial function and decreases mitochondrial PE levels; PISD overexpression alleviates the NASH-like phenotype in Cds2-deficient mice and normalizes mitochondrial morphology and function, demonstrating that PISD activity downstream of CDS2 maintains mitochondrial PE homeostasis in vivo.","method":"Liver-specific Cds2 KO mice, PISD overexpression in vivo, mitochondrial PE measurement, mitochondrial morphology and function assays, NASH phenotype assessment","journal":"Science bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — genetic rescue with PISD overexpression in vivo with multiple readouts, single lab","pmids":["36546079"],"is_preprint":false}],"current_model":"PISD encodes phosphatidylserine decarboxylase, localized primarily to the inner mitochondrial membrane (with an alternatively spliced isoform that also targets lipid droplets), where it catalyzes autocatalytic self-processing to generate the active heteromeric enzyme that decarboxylates phosphatidylserine to phosphatidylethanolamine (PE); mitochondrial PE produced by PISD is essential for maintaining normal mitochondrial morphology (preventing fragmentation), supporting autophagosome biogenesis, regulating mitochondrial respiration and dynamics, controlling mPTP opening via SPG7, and linking to ferroptosis via STAT3/GPX4 signaling, with PS substrate delivered to the IMM by the conserved SLMO/SLMO2 lipid transfer protein."},"narrative":{"teleology":[{"year":2002,"claim":"Before direct characterization, PISD enzymatic activity was shown to exhibit tissue- and age-dependent substrate selectivity in brain mitochondria, establishing that PS decarboxylation is not uniform across tissues.","evidence":"In vitro enzymatic activity assays with defined PS substrates from rat cerebellar and cortical mitochondrial fractions","pmids":["12391587"],"confidence":"Medium","gaps":["Single lab biochemical study","No genetic perturbation to confirm in vivo relevance","Molecular basis of substrate selectivity unknown"]},{"year":2005,"claim":"Genetic ablation established that PISD-dependent mitochondrial PE synthesis is essential for embryonic viability and normal mitochondrial morphology, and that the CDP-ethanolamine pathway cannot compensate during development.","evidence":"PISD knockout mice with EM, confocal microscopy, and radiolabeled PE synthesis assays","pmids":["16192276"],"confidence":"High","gaps":["Mechanism by which PE loss causes mitochondrial fragmentation not defined","Cell-type-specific requirements not resolved","Whether partial loss of function is tolerable in vivo unknown"]},{"year":2018,"claim":"PISD was linked to autophagosome biogenesis: mitochondrial PE produced at MAM contact sites supports LC3-II lipidation and autophagy flux downstream of mTOR inhibition, connecting mitochondrial phospholipid metabolism to autophagy.","evidence":"Complex I-deficient cells, mTOR inhibitor treatment, MAM quantification, phospholipid mass spectrometry, and autophagy flux assays","pmids":["30157433"],"confidence":"High","gaps":["Direct PE transfer from mitochondria to autophagosomes not demonstrated","Whether PISD-derived PE is specifically required versus total cellular PE unclear"]},{"year":2018,"claim":"Human disease mutations were shown to impair PISD function: a p.Cys266Tyr variant caused mitochondrial fragmentation and apoptotic sensitivity in patient fibroblasts, rescued by ethanolamine supplementation, while a founder deletion caused Liberfarb syndrome through aberrant splicing.","evidence":"Trio-exome sequencing, patient fibroblast functional assays, minigene splicing assays, ethanolamine rescue","pmids":["30488656","31263216"],"confidence":"Medium","gaps":["Limited number of families studied","Genotype-phenotype correlation across the mutation spectrum incomplete","No animal model recapitulating Liberfarb syndrome phenotype"]},{"year":2019,"claim":"The autocatalytic self-processing mechanism of PISD was directly demonstrated as required for enzymatic activity: a paternal variant impaired proenzyme cleavage while a maternal variant caused aberrant splicing, and both lyso-PE supplementation and genetic complementation rescued mitochondrial and lysosomal morphology.","evidence":"PS-to-PE conversion assays in patient fibroblasts, autocatalytic processing analysis, oxygen consumption measurement, lyso-PE rescue","pmids":["30858161"],"confidence":"High","gaps":["Structural determinants of autocatalytic cleavage in human PISD not resolved at atomic level","Whether processing intermediates have regulatory roles unknown"]},{"year":2021,"claim":"An alternatively spliced PISD isoform (PISD-LD) was discovered to target lipid droplets rather than mitochondria, with nutritional state controlling isoform localization, expanding PISD function beyond mitochondria to triacylglycerol metabolism.","evidence":"Splice variant characterization, subcellular fractionation, fluorescence localization under lipid storage versus consumption conditions, siRNA depletion","pmids":["33593792"],"confidence":"High","gaps":["Enzymatic activity and substrate specificity of PISD-LD on lipid droplets not characterized","Physiological significance of dual targeting in vivo unknown"]},{"year":2024,"claim":"The conserved PS delivery pathway to PISD was reconstituted: SLMO/SLMO2 transfers PS from the OMM to the IMM inner boundary membrane domain, establishing a PSS→SLMO→PISD genetic pathway required for mitochondrial morphology.","evidence":"Forward genetic screen in Drosophila, epistasis analysis, human SLMO2 complementation, mitochondrial morphology assays","pmids":["39680501"],"confidence":"High","gaps":["Biochemical mechanism of SLMO-mediated PS transfer not resolved","Whether additional lipid transfer proteins contribute in mammalian cells unknown"]},{"year":2025,"claim":"Downstream signaling axes of PISD-derived PE were defined: PISD depletion reduces STAT3 phosphorylation and GPX4 expression to promote ferroptosis, while PISD overexpression upregulates SPG7 to inhibit mPTP opening and necroptosis, revealing PE as a signaling-competent lipid beyond structural roles.","evidence":"PISD knockdown/overexpression in gastric cancer and HaCaT cells, STAT3/GPX4 immunoblots, lipid peroxidation assays, mPTP opening assays, pharmacological rescue with Fer-1 and ML115","pmids":["41899452","40780696"],"confidence":"Medium","gaps":["Whether PE directly modulates STAT3 or acts indirectly through membrane composition changes unknown","SPG7 transcriptional regulation by PISD not mechanistically defined","Single-lab findings for each axis"]},{"year":2025,"claim":"PISD deficiency was shown to broadly compromise mitochondrial bioenergetics—reducing ETC complex I/IV abundance, increasing superoxide, promoting fission and mitophagy, and suppressing mTOR-dependent proliferation—while aging reduces ER-mitochondria contacts to limit PS delivery to PISD, impairing autophagy and causing giant mitochondria accumulation.","evidence":"PISD siRNA in hepatocarcinoma cells with Seahorse respiration, ETC immunoblots; aged mouse cardiomyocytes with ER-Mito contact quantification, PE measurement, LACTB modulation","pmids":["41360863","40254645"],"confidence":"Medium","gaps":["Relative contribution of reduced PE versus secondary metabolic compensation not dissected","LACTB mechanism of PISD enhancement not defined","In vivo validation of aging-PISD-autophagy axis in non-cardiac tissues lacking"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of mammalian PISD and its autocatalytic mechanism, how PE produced by PISD is distributed from the IMM to autophagosomes and other membranes, the physiological significance of the lipid droplet isoform in vivo, and genotype-phenotype relationships across the spectrum of human PISD variants.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure of mammalian PISD","PE export route from IMM to extra-mitochondrial membranes undefined","PISD-LD isoform function in animal models untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[0,3,9,11]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3,6,11]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,6,9,11,17]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,11,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,7,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,14,15]}],"complexes":[],"partners":["SLMO2","SPG7","LACTB"],"other_free_text":[]},"mechanistic_narrative":"PISD encodes phosphatidylserine decarboxylase, the inner mitochondrial membrane enzyme that converts phosphatidylserine (PS) to phosphatidylethanolamine (PE) through an autocatalytic self-processing mechanism that generates the active pyruvoyl-containing heteromer [PMID:30858161, PMID:16192276]. Mitochondrial PE produced by PISD is essential for maintaining mitochondrial cristae morphology, electron transport chain integrity (complexes I and IV), and mitochondrial respiration, and cannot be fully compensated by the CDP-ethanolamine pathway; PS substrate is delivered to the IMM by the conserved SLMO/SLMO2 lipid transfer protein [PMID:16192276, PMID:39680501, PMID:41360863]. PISD-derived PE also supports autophagosome membrane biogenesis downstream of mTOR inhibition, regulates ferroptosis susceptibility via a STAT3–GPX4 axis, and controls mPTP opening through SPG7 [PMID:30157433, PMID:41899452, PMID:40780696]. Loss-of-function PISD variants cause Liberfarb syndrome, a multisystem disorder featuring retinal degeneration, sensorineural hearing loss, microcephaly, and skeletal dysplasia [PMID:31263216, PMID:30488656]."},"prefetch_data":{"uniprot":{"accession":"Q9UG56","full_name":"Phosphatidylserine decarboxylase proenzyme, mitochondrial","aliases":[],"length_aa":409,"mass_kda":46.7,"function":"Catalyzes the formation of phosphatidylethanolamine (PtdEtn) from phosphatidylserine (PtdSer) (PubMed:30488656, PubMed:30858161). Plays a central role in phospholipid metabolism and in the interorganelle trafficking of phosphatidylserine. May be involved in lipid droplet biogenesis at the endoplasmic reticulum membrane (By similarity)","subcellular_location":"Mitochondrion inner membrane; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/Q9UG56/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PISD","classification":"Common Essential","n_dependent_lines":604,"n_total_lines":1208,"dependency_fraction":0.5},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PISD","total_profiled":1310},"omim":[{"mim_id":"618889","title":"LIBERFARB SYNDROME; LIBF","url":"https://www.omim.org/entry/618889"},{"mim_id":"614939","title":"PHOSPHOGLYCERATE MUTASE FAMILY, MEMBER 5; PGAM5","url":"https://www.omim.org/entry/614939"},{"mim_id":"612770","title":"PHOSPHATIDYLSERINE DECARBOXYLASE; PISD","url":"https://www.omim.org/entry/612770"},{"mim_id":"608440","title":"LACTAMASE, BETA; LACTB","url":"https://www.omim.org/entry/608440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PISD"},"hgnc":{"alias_symbol":["dJ858B16.2","PSDC"],"prev_symbol":[]},"alphafold":{"accession":"Q9UG56","domains":[{"cath_id":"-","chopping":"184-222_237-409","consensus_level":"high","plddt":89.3827,"start":184,"end":409}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UG56","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UG56-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UG56-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PISD","jax_strain_url":"https://www.jax.org/strain/search?query=PISD"},"sequence":{"accession":"Q9UG56","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UG56.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UG56/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UG56"}},"corpus_meta":[{"pmid":"16192276","id":"PMC_16192276","title":"Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16192276","citation_count":221,"is_preprint":false},{"pmid":"8899637","id":"PMC_8899637","title":"Pelvic visceral input into the nucleus gracilis is largely mediated by the postsynaptic dorsal column pathway.","date":"1996","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/8899637","citation_count":151,"is_preprint":false},{"pmid":"6323643","id":"PMC_6323643","title":"Postsynaptic dorsal column pathway of the rat. 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fragmented, misshapen mitochondria, demonstrating that mitochondrial PE synthesis via PS decarboxylation is required for normal mitochondrial structure and cannot be compensated by the CDP-ethanolamine pathway during development.\",\n      \"method\": \"Knockout mouse generation, electron microscopy, fluorescence confocal microscopy, radiolabeled PE synthesis assays, immunoblotting of compensatory pathway enzymes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic KO with multiple orthogonal readouts (EM, confocal, biochemical assays), highly cited foundational study\",\n      \"pmids\": [\"16192276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PISD activity and mitochondrial-associated membrane (MAM) contacts are required for maximal autophagy induction downstream of mTOR inhibition; complex I dysfunction suppresses autophagy by preventing the increase in MAMs and limiting PISD-dependent mitochondrial PE (mtPE) production needed to support autophagosome biogenesis.\",\n      \"method\": \"Genetic defects in complex I, phenformin treatment, mTOR inhibitor treatment, phospholipid mass spectrometry, MAM quantification, autophagy flux assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking PISD activity to MAM contacts and autophagy, with pharmacological and genetic perturbations\",\n      \"pmids\": [\"30157433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The missense variant p.(Cys266Tyr) in PISD causes impaired phosphatidylserine decarboxylase function, leading to fragmented mitochondrial morphology in patient fibroblasts and increased apoptotic sensitivity; ethanolamine supplementation restores cell viability, confirming the causal role of reduced PE synthesis.\",\n      \"method\": \"Trio-exome sequencing, patient-derived fibroblast analysis, mitochondrial morphology imaging, caspase-3/7 activation assays, ethanolamine rescue\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient fibroblast functional validation with multiple readouts, single study\",\n      \"pmids\": [\"30488656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Compound heterozygous PISD variants cause impaired PS-to-PE conversion in the inner mitochondrial membrane (IMM); one paternal variant impairs autocatalytic self-processing of the PISD precursor required for enzymatic activity, while the maternal variant causes aberrant splicing; lyso-PE supplementation or genetic complementation restores mitochondrial and lysosome morphology.\",\n      \"method\": \"Exome sequencing, PS-to-PE conversion assays in patient fibroblasts, mitochondrial morphology imaging, oxygen consumption rate measurement, lyso-PE rescue, genetic complementation, splice product analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity directly measured, autocatalytic processing mechanism identified, multiple orthogonal rescue experiments\",\n      \"pmids\": [\"30858161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A founder 10-bp deletion in PISD immediately upstream of the last exon causes aberrant splicing of PISD transcripts in HEK293T cells, establishing loss of functional PISD as the genetic basis of Liberfarb syndrome (retinal degeneration, sensorineural hearing loss, microcephaly, skeletal dysplasia).\",\n      \"method\": \"Exome sequencing, autozygosity mapping, minigene construct splicing assay in HEK293T cells, qPCR, Sanger sequencing of paraffin-embedded tissue\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing mechanism validated in cell-based minigene assay, single study\",\n      \"pmids\": [\"31263216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PISD overexpression reduces tumor-initiating potential of breast cancer cells in mammosphere assays and mouse xenograft models and regulates multiple aspects of mitochondrial function; PISD is downregulated ~8-fold in migratory/tumor-initiating cells.\",\n      \"method\": \"Microfluidic migration isolation, whole-transcriptome sequencing, PISD overexpression, mammosphere assay, mouse xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss/gain of function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"29321615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PISD localizes to the inner mitochondrial membrane and to lipid droplets via an alternatively spliced isoform (PISD-LD); sub-cellular targeting is controlled by a segment distinct from the catalytic domain and is regulated by nutritional state (lipid storage conditions favor lipid droplet targeting, lipid consumption favors mitochondrial targeting); depletion of both forms impairs triacylglycerol synthesis during fatty acid challenge.\",\n      \"method\": \"Alternative splice variant characterization, sub-cellular fractionation, fluorescence localization, nutritional perturbation, siRNA depletion, triacylglycerol synthesis assay\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional consequence, multiple conditions tested\",\n      \"pmids\": [\"33593792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TFAM knockdown reduces PISD expression through a mechanism involving increased NAD+/NADH ratio, upregulation of SIRT1, deacetylation of p53 at lysine 382, and reduced p53 transcriptional activation of the PISD enhancer; decreased PISD then reduces LC3-II levels and impairs autophagy.\",\n      \"method\": \"TFAM siRNA knockdown, PISD siRNA knockdown, LC3-II immunoblot, NAD+/NADH measurement, SIRT1 activity assay, p53 acetylation analysis, luciferase/ChIP-based transcription assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established through multiple biochemical measurements in single lab\",\n      \"pmids\": [\"32093281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGF-β1-induced myofibroblast transition reduces PISD expression in mitochondria; PISD knockdown alone (without TGF-β1) is sufficient to increase α-smooth muscle actin mRNA and collagen production, placing PISD activity upstream of fibrogenesis through phospholipid metabolism.\",\n      \"method\": \"TGF-β1 stimulation, lipidomic analysis, PISD siRNA knockdown, α-SMA mRNA quantification, collagen production assay\",\n      \"journal\": \"Journal of clinical biochemistry and nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"35400823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Brain mitochondrial PISD (phosphatidylserine decarboxylase) activity shows tissue-dependent and age-dependent substrate preferences based on DHA (22:6n-3) content of the phosphatidylserine substrate; cerebellar PISD activity is specifically inhibited during aging.\",\n      \"method\": \"Mitochondrial fraction isolation from rat cerebral cortex and cerebellum, enzymatic activity assays with PS substrates of defined fatty acid composition\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic activity assays with defined substrates, single lab\",\n      \"pmids\": [\"12391587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PISD downregulation by high uric acid (via inhibited STAT3 phosphorylation) reduces mitochondrial PE levels and impairs mitochondrial respiration, inducing apoptosis; PISD overexpression or lyso-PE supplementation rescues these effects in vitro.\",\n      \"method\": \"Lipidomic analysis of mitochondria, PISD overexpression, lyso-PE supplementation, STAT3 phosphorylation assays, mitochondrial respiration measurement, apoptosis assays\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal rescue approaches, single lab\",\n      \"pmids\": [\"37502610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLMO (the Drosophila ortholog of SLMO2) specifically transfers phosphatidylserine from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM) within the inner boundary membrane domain, providing substrate for PISD to synthesize PE; genetic evidence places PSS→SLMO→PISD in a conserved pathway required for mitochondrial morphology.\",\n      \"method\": \"Forward genetic screen in Drosophila, epistasis analysis of PSS-SLMO-PISD pathway, mitochondrial morphology assays, SLMO2 human complementation\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic epistasis with forward screen, pathway reconstituted in vivo, conservation validated in human cells\",\n      \"pmids\": [\"39680501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Novel compound heterozygous PISD missense variants p.(Ser190Leu) and p.(His267Tyr) likely impair PISD autocatalytic self-processing and/or PE biosynthesis based on structural homology to E. coli ortholog; patient fibroblasts show significantly higher mitochondrial fragmentation compared to controls.\",\n      \"method\": \"Trio genome sequencing, fibroblast mitochondrial morphology imaging with 2-deoxyglucose stress, structural modeling using E. coli PISD ortholog crystal data\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional fibroblast data combined with structural modeling, single study\",\n      \"pmids\": [\"38801004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PISD deficiency in HEPA1-6 hepatocellular carcinoma cells impairs mitochondrial fatty acid and glucose oxidation, reduces electron transport chain complex I and IV abundance, increases mitochondrial superoxide, augments mitochondrial fission and mitophagy, and reduces cell proliferation via reduced mTOR signaling; peroxisomal fat oxidation and anaerobic glycolysis partially compensate.\",\n      \"method\": \"PISD siRNA silencing, mitochondrial respiration assays (Seahorse), ETC complex abundance (immunoblot), mitochondrial dynamics imaging, cell proliferation assays, mTOR signaling assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal phenotypic readouts from single lab KD experiment\",\n      \"pmids\": [\"41360863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PISD depletion in gastric cancer cells reduces PE levels, decreases STAT3 phosphorylation and GPX4 expression, increases lipid peroxidation and iron accumulation, enhancing ferroptosis; Ferrostatin-1, STAT3 activator ML115, or lyso-PE supplementation partially rescues PISD knockdown-induced ferroptosis, defining a PISD→STAT3→GPX4 axis.\",\n      \"method\": \"PISD knockdown, PE quantification, STAT3 phosphorylation immunoblot, GPX4 immunoblot, lipid peroxidation assays, ferroptosis rescue with Fer-1/ML115/LPE, xenograft tumor growth\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established with pharmacological rescues, single lab\",\n      \"pmids\": [\"41899452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PISD overexpression directly upregulates SPG7 (a critical mPTP component) expression, inhibits mitochondrial permeability transition pore opening, and reverses necroptosis induced by nano-zinc oxide in inflammatory HaCaT cells, establishing a PISD→SPG7→mPTP axis.\",\n      \"method\": \"PISD overexpression, SPG7 overexpression, mPTP opening assay, p-MLKL immunoblot, mitochondrial morphology imaging\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"40780696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Reduction in ER-mitochondria contacts in aged cardiomyocytes impairs PS lipid transport to mitochondria; combined with PISD deficiency, this reduces PE production, impairing autophagosomal membrane formation and autophagic flux, leading to accumulation of dysfunctional giant mitochondria; modulating LACTB expression to enhance PISD activity restores mitochondrial homeostasis.\",\n      \"method\": \"Aged mouse models, etoposide-induced senescence, ER-Mito contact quantification, PE measurement, autophagy flux assays, LACTB manipulation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple models and mechanistic interventions, single lab\",\n      \"pmids\": [\"40254645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hepatic CDS2 deficiency impairs mitochondrial function and decreases mitochondrial PE levels; PISD overexpression alleviates the NASH-like phenotype in Cds2-deficient mice and normalizes mitochondrial morphology and function, demonstrating that PISD activity downstream of CDS2 maintains mitochondrial PE homeostasis in vivo.\",\n      \"method\": \"Liver-specific Cds2 KO mice, PISD overexpression in vivo, mitochondrial PE measurement, mitochondrial morphology and function assays, NASH phenotype assessment\",\n      \"journal\": \"Science bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue with PISD overexpression in vivo with multiple readouts, single lab\",\n      \"pmids\": [\"36546079\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PISD encodes phosphatidylserine decarboxylase, localized primarily to the inner mitochondrial membrane (with an alternatively spliced isoform that also targets lipid droplets), where it catalyzes autocatalytic self-processing to generate the active heteromeric enzyme that decarboxylates phosphatidylserine to phosphatidylethanolamine (PE); mitochondrial PE produced by PISD is essential for maintaining normal mitochondrial morphology (preventing fragmentation), supporting autophagosome biogenesis, regulating mitochondrial respiration and dynamics, controlling mPTP opening via SPG7, and linking to ferroptosis via STAT3/GPX4 signaling, with PS substrate delivered to the IMM by the conserved SLMO/SLMO2 lipid transfer protein.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PISD encodes phosphatidylserine decarboxylase, the inner mitochondrial membrane enzyme that converts phosphatidylserine (PS) to phosphatidylethanolamine (PE) through an autocatalytic self-processing mechanism that generates the active pyruvoyl-containing heteromer [PMID:30858161, PMID:16192276]. Mitochondrial PE produced by PISD is essential for maintaining mitochondrial cristae morphology, electron transport chain integrity (complexes I and IV), and mitochondrial respiration, and cannot be fully compensated by the CDP-ethanolamine pathway; PS substrate is delivered to the IMM by the conserved SLMO/SLMO2 lipid transfer protein [PMID:16192276, PMID:39680501, PMID:41360863]. PISD-derived PE also supports autophagosome membrane biogenesis downstream of mTOR inhibition, regulates ferroptosis susceptibility via a STAT3–GPX4 axis, and controls mPTP opening through SPG7 [PMID:30157433, PMID:41899452, PMID:40780696]. Loss-of-function PISD variants cause Liberfarb syndrome, a multisystem disorder featuring retinal degeneration, sensorineural hearing loss, microcephaly, and skeletal dysplasia [PMID:31263216, PMID:30488656].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Before direct characterization, PISD enzymatic activity was shown to exhibit tissue- and age-dependent substrate selectivity in brain mitochondria, establishing that PS decarboxylation is not uniform across tissues.\",\n      \"evidence\": \"In vitro enzymatic activity assays with defined PS substrates from rat cerebellar and cortical mitochondrial fractions\",\n      \"pmids\": [\"12391587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab biochemical study\", \"No genetic perturbation to confirm in vivo relevance\", \"Molecular basis of substrate selectivity unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic ablation established that PISD-dependent mitochondrial PE synthesis is essential for embryonic viability and normal mitochondrial morphology, and that the CDP-ethanolamine pathway cannot compensate during development.\",\n      \"evidence\": \"PISD knockout mice with EM, confocal microscopy, and radiolabeled PE synthesis assays\",\n      \"pmids\": [\"16192276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PE loss causes mitochondrial fragmentation not defined\", \"Cell-type-specific requirements not resolved\", \"Whether partial loss of function is tolerable in vivo unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PISD was linked to autophagosome biogenesis: mitochondrial PE produced at MAM contact sites supports LC3-II lipidation and autophagy flux downstream of mTOR inhibition, connecting mitochondrial phospholipid metabolism to autophagy.\",\n      \"evidence\": \"Complex I-deficient cells, mTOR inhibitor treatment, MAM quantification, phospholipid mass spectrometry, and autophagy flux assays\",\n      \"pmids\": [\"30157433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PE transfer from mitochondria to autophagosomes not demonstrated\", \"Whether PISD-derived PE is specifically required versus total cellular PE unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Human disease mutations were shown to impair PISD function: a p.Cys266Tyr variant caused mitochondrial fragmentation and apoptotic sensitivity in patient fibroblasts, rescued by ethanolamine supplementation, while a founder deletion caused Liberfarb syndrome through aberrant splicing.\",\n      \"evidence\": \"Trio-exome sequencing, patient fibroblast functional assays, minigene splicing assays, ethanolamine rescue\",\n      \"pmids\": [\"30488656\", \"31263216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited number of families studied\", \"Genotype-phenotype correlation across the mutation spectrum incomplete\", \"No animal model recapitulating Liberfarb syndrome phenotype\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The autocatalytic self-processing mechanism of PISD was directly demonstrated as required for enzymatic activity: a paternal variant impaired proenzyme cleavage while a maternal variant caused aberrant splicing, and both lyso-PE supplementation and genetic complementation rescued mitochondrial and lysosomal morphology.\",\n      \"evidence\": \"PS-to-PE conversion assays in patient fibroblasts, autocatalytic processing analysis, oxygen consumption measurement, lyso-PE rescue\",\n      \"pmids\": [\"30858161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of autocatalytic cleavage in human PISD not resolved at atomic level\", \"Whether processing intermediates have regulatory roles unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An alternatively spliced PISD isoform (PISD-LD) was discovered to target lipid droplets rather than mitochondria, with nutritional state controlling isoform localization, expanding PISD function beyond mitochondria to triacylglycerol metabolism.\",\n      \"evidence\": \"Splice variant characterization, subcellular fractionation, fluorescence localization under lipid storage versus consumption conditions, siRNA depletion\",\n      \"pmids\": [\"33593792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic activity and substrate specificity of PISD-LD on lipid droplets not characterized\", \"Physiological significance of dual targeting in vivo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The conserved PS delivery pathway to PISD was reconstituted: SLMO/SLMO2 transfers PS from the OMM to the IMM inner boundary membrane domain, establishing a PSS→SLMO→PISD genetic pathway required for mitochondrial morphology.\",\n      \"evidence\": \"Forward genetic screen in Drosophila, epistasis analysis, human SLMO2 complementation, mitochondrial morphology assays\",\n      \"pmids\": [\"39680501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of SLMO-mediated PS transfer not resolved\", \"Whether additional lipid transfer proteins contribute in mammalian cells unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Downstream signaling axes of PISD-derived PE were defined: PISD depletion reduces STAT3 phosphorylation and GPX4 expression to promote ferroptosis, while PISD overexpression upregulates SPG7 to inhibit mPTP opening and necroptosis, revealing PE as a signaling-competent lipid beyond structural roles.\",\n      \"evidence\": \"PISD knockdown/overexpression in gastric cancer and HaCaT cells, STAT3/GPX4 immunoblots, lipid peroxidation assays, mPTP opening assays, pharmacological rescue with Fer-1 and ML115\",\n      \"pmids\": [\"41899452\", \"40780696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PE directly modulates STAT3 or acts indirectly through membrane composition changes unknown\", \"SPG7 transcriptional regulation by PISD not mechanistically defined\", \"Single-lab findings for each axis\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PISD deficiency was shown to broadly compromise mitochondrial bioenergetics—reducing ETC complex I/IV abundance, increasing superoxide, promoting fission and mitophagy, and suppressing mTOR-dependent proliferation—while aging reduces ER-mitochondria contacts to limit PS delivery to PISD, impairing autophagy and causing giant mitochondria accumulation.\",\n      \"evidence\": \"PISD siRNA in hepatocarcinoma cells with Seahorse respiration, ETC immunoblots; aged mouse cardiomyocytes with ER-Mito contact quantification, PE measurement, LACTB modulation\",\n      \"pmids\": [\"41360863\", \"40254645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of reduced PE versus secondary metabolic compensation not dissected\", \"LACTB mechanism of PISD enhancement not defined\", \"In vivo validation of aging-PISD-autophagy axis in non-cardiac tissues lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of mammalian PISD and its autocatalytic mechanism, how PE produced by PISD is distributed from the IMM to autophagosomes and other membranes, the physiological significance of the lipid droplet isoform in vivo, and genotype-phenotype relationships across the spectrum of human PISD variants.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of mammalian PISD\", \"PE export route from IMM to extra-mitochondrial membranes undefined\", \"PISD-LD isoform function in animal models untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0, 3, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3, 6, 11]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 6, 9, 11, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 11, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 7, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 14, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SLMO2\",\n      \"SPG7\",\n      \"LACTB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}