{"gene":"AARS2","run_date":"2026-06-09T22:02:35","timeline":{"discoveries":[{"year":2024,"finding":"AARS2 (and AARS1) directly bind L-lactate with micromolar affinity and catalyze ATP-dependent lysine lactylation, functioning as intracellular L-lactate sensors and lactyltransferases. In response to elevated L-lactate, AARS2 associates with cGAS and mediates its lactylation and inactivation in cells and in mice, abolishing cGAS liquid-like phase separation and DNA sensing.","method":"Biochemical binding assays, in vitro lactylation reconstitution, Co-IP (AARS2–cGAS association), genetic code expansion orthogonal system for lactyl-lysine incorporation, lactyl-mimetic and lactyl-resistant knock-in mouse models, in vitro and in vivo phase separation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of lactylation activity, mutagenesis via knock-in models, multiple orthogonal methods (binding assays, Co-IP, cell-based, in vivo), replicated across cells and mice","pmids":["39322678"],"is_preprint":false},{"year":2025,"finding":"AARS2 lactylates and inactivates carnitine palmitoyl transferase 2 (CPT2), resulting in free fatty acid accumulation that activates PPARγ and potentiates FSH-driven follicle development. AARS2 also promotes PDHA1 inactivation via lactylation, stimulating granulosa cell proliferation and primordial follicle development. GC-specific AARS2 overexpression accelerates follicle depletion, while AARS2 ablation or β-alanine treatment prevents folliculogenesis and POI traits in mice.","method":"AARS2 gain-of-function mutation characterization, in vitro lactylation assays on CPT2 and PDHA1, GC-specific AARS2 overexpression and knockout mouse models, metabolic measurements (FFA, PPARγ activation)","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct lactylation assays on substrates combined with in vivo mouse models, single lab, multiple orthogonal methods","pmids":["40301335"],"is_preprint":false},{"year":2026,"finding":"In a homozygous Aars2 R194C knock-in mouse model (mimicking human R199C pathogenic variant), the mutation increases lysine lactylation of PDHA1 and CPT2, reduces their activity, impairs mitochondrial respiration in granulosa cells, activates mTORC1 signaling, and causes premature follicle activation and POI. SIRT3 (mitochondrial de-lactylase) loss mitigated these abnormalities; pharmacological inhibition of PDHA1/CPT2 in WT mice phenocopied the knock-in.","method":"Homozygous knock-in mouse model, lysine lactylation measurements on endogenous substrates, mitochondrial respiration assays, mTORC1 pathway analysis, pharmacological inhibition rescue experiments","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in model with multiple orthogonal functional assays, single lab, no independent replication yet","pmids":["41832996"],"is_preprint":false},{"year":2025,"finding":"AARS2 overexpression in cardiomyocytes suppresses apoptosis and mitochondrial ROS production and shifts cellular metabolism from oxidative phosphorylation toward glycolysis. Ribosome profiling (Ribo-Seq) revealed that Aars2 overexpression increases PKM2 protein translation and promotes the PKM2 dimer-to-tetramer ratio favoring glycolysis. PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency, defining an AARS2–PKM2 signaling axis.","method":"Cardiomyocyte-specific Aars2 deletion and overexpression mouse models, Ribo-Seq (translational profiling), PKM2 dimer/tetramer ratio assays, pharmacological rescue with TEPP-46, cardiac function measurements","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including Ribo-Seq and genetic/pharmacological rescue, single lab","pmids":["40371904"],"is_preprint":false},{"year":2023,"finding":"PCBP1 interacts with the Aars2 transcript to mediate its alternative splicing in cardiomyocytes. Cardiomyocyte-specific deletion of Pcbp1 causes aberrant alternative splicing and premature termination of Aars2, reducing oxidative phosphorylation and triggering mitonuclear communication and the unfolded protein response. Aars2 mutant mice with exon-16 skipping recapitulate heart developmental defects, and loss of Pcbp1 or Aars2 reduces the mitochondrial-encoded proteome.","method":"Cardiomyocyte-specific Pcbp1 knockout mice, Aars2 exon-16 skipping mutant mice, RNA splicing analysis, oxidative phosphorylation measurements, proteomics of mitochondrial-encoded proteins, UPR pathway analysis","journal":"Nature cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse models with multiple orthogonal readouts (splicing, proteomics, OXPHOS), single lab, peer-reviewed publication","pmids":["42010330","37293078"],"is_preprint":false},{"year":2015,"finding":"Structural modeling of AARS2 predicts that the cardiomyopathy-causing R592W mutation resides in the editing domain responsible for deacylating mischarged tRNAs, while leukodystrophy mutations affect other domains; all mutations are predicted to reduce aminoacylation activity because all AARS2 domains contribute to tRNA binding. The cardiomyopathy allele is predicted to severely compromise aminoacylation, whereas leukodystrophy allele combinations retain partial activity.","method":"Structural homology modeling of AARS2 domains, mapping of disease mutations onto predicted 3D structure","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural modeling only, no experimental biochemical validation reported in the abstract","pmids":["25705216"],"is_preprint":false},{"year":2019,"finding":"A homozygous AARS2 mutation (p.G113R) in the aminoacylation domain significantly reduced ATP production in patient-derived cells compared to wild-type (3.58 vs 6.96 fmol/min/cell), consistent with impaired mitochondrial translation due to defective aminoacylation of tRNA-Ala.","method":"Seahorse XFe96 metabolic analyzer measuring oxygen consumption, ATP production, and extracellular acidification rate in patient cells carrying the AARS2 mutation vs. wild-type","journal":"Fertility and sterility","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional metabolic assay in patient-derived cells, single lab, single method","pmids":["31280959"],"is_preprint":false},{"year":2020,"finding":"Yeast complementation assays demonstrated that the AARS2 p.Phe131del variant dramatically impairs AARS2 gene function, while p.Ile328Met is a hypomorphic allele, establishing that these variants cause loss of AARS2 function sufficient to produce ataxia without leukoencephalopathy.","method":"Yeast complementation assay using AARS2 variants (p.Phe131del and p.Ile328Met)","journal":"Cerebellum (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional complementation assay in model organism, single lab, single method, directly tests variant activity","pmids":["31705293"],"is_preprint":false},{"year":2026,"finding":"AARS2 catalyzes lactylation of AP-2γ at K444, enhancing TRIM28 binding and promoting K63-linked ubiquitination and nuclear translocation of AP-2γ to facilitate HCC tumor progression. AARS2 knockdown in HCT116 colon cancer cells reduced extracellular lactate accumulation and attenuated global protein lactylation, and upregulated cGAS-STING pathway genes (CCL5, CXCL10, IFNB1).","method":"Mass spectrometry identification of lactylation site on AP-2γ (K444), Co-IP of AP-2γ–TRIM28, ubiquitination assays, AARS2 knockdown in cancer cell lines, extracellular lactate measurement, qRT-PCR of immune genes","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific lactylation identified by MS, Co-IP interaction, functional knockdown with multiple readouts, single lab","pmids":["42114979"],"is_preprint":false}],"current_model":"AARS2 is a mitochondrial alanyl-tRNA synthetase that charges tRNA-Ala with alanine to support mitochondrial protein synthesis, but it also functions as an intracellular L-lactate sensor and lactyltransferase: it binds L-lactate with micromolar affinity and catalyzes ATP-dependent lysine lactylation of substrates including cGAS (suppressing innate immune signaling), CPT2 and PDHA1 (impairing mitochondrial metabolism to drive premature ovarian insufficiency), and AP-2γ (promoting oncogenic signaling); in the heart, AARS2 additionally regulates PKM2 protein translation via ribosome engagement to shift cardiomyocyte metabolism toward glycolysis under ischemic stress, and its cardiac-specific splicing is controlled by the RNA-binding protein PCBP1."},"narrative":{"mechanistic_narrative":"AARS2 is a mitochondrial alanyl-tRNA synthetase whose aminoacylation activity supports mitochondrial protein synthesis, and which additionally functions as an intracellular L-lactate sensor and lactyltransferase [PMID:39322678, PMID:31280959]. AARS2 binds L-lactate with micromolar affinity and catalyzes ATP-dependent lysine lactylation of target proteins; acting on cGAS, it lactylates and inactivates the sensor, abolishing its phase separation and DNA-sensing activity to suppress innate immune signaling [PMID:39322678]. Through lactylation of metabolic enzymes CPT2 and PDHA1, AARS2 inactivates both, driving free fatty acid accumulation, PPARγ activation, impaired mitochondrial respiration, mTORC1 activation, and premature follicle activation that underlies premature ovarian insufficiency; the de-lactylase SIRT3 opposes these effects [PMID:40301335, PMID:41832996]. In cancer, AARS2 lactylates AP-2γ at K444 to enhance TRIM28 binding, K63-linked ubiquitination, and nuclear translocation, promoting tumor progression while restraining cGAS-STING immune gene expression [PMID:42114979]. In the heart, AARS2 increases PKM2 translation and shifts cardiomyocyte metabolism toward glycolysis to limit apoptosis and ROS under stress, defining an AARS2-PKM2 axis [PMID:40371904], and its cardiomyocyte splicing is controlled by the RNA-binding protein PCBP1, with aberrant splicing reducing oxidative phosphorylation and the mitochondrial-encoded proteome [PMID:42010330, PMID:37293078]. Disease-associated AARS2 mutations compromise aminoacylation activity, reducing ATP production in patient cells and producing loss of function in complementation assays, linking AARS2 to cardiomyopathy, leukodystrophy, and ataxia phenotypes [PMID:25705216, PMID:31280959, PMID:31705293].","teleology":[{"year":2015,"claim":"Established how disease mutations map onto AARS2 functional domains, framing the synthetase's aminoacylation and editing activities as the basis for genotype-phenotype differences in cardiomyopathy versus leukodystrophy.","evidence":"Structural homology modeling mapping disease mutations onto predicted 3D domains","pmids":["25705216"],"confidence":"Low","gaps":["Computational modeling only, no experimental biochemical validation of predicted activity","Domain contributions to tRNA binding not directly measured"]},{"year":2019,"claim":"Demonstrated functionally that an aminoacylation-domain mutation impairs mitochondrial energy output, confirming AARS2 loss of function reduces ATP production via defective tRNA-Ala charging.","evidence":"Seahorse metabolic analysis of patient-derived cells versus wild-type","pmids":["31280959"],"confidence":"Medium","gaps":["Single method, single mutation","Direct measurement of aminoacylation activity not shown"]},{"year":2020,"claim":"Confirmed pathogenicity and severity ranking of specific AARS2 variants, establishing thresholds of lost function sufficient to produce ataxia without leukoencephalopathy.","evidence":"Yeast complementation assay with p.Phe131del and p.Ile328Met variants","pmids":["31705293"],"confidence":"Medium","gaps":["Single assay in heterologous system","Mechanistic link to neuronal phenotype not addressed"]},{"year":2023,"claim":"Revealed an upstream regulatory layer controlling cardiac AARS2 expression, showing PCBP1-mediated alternative splicing is required for proper Aars2 transcript processing and mitochondrial translation in the heart.","evidence":"Cardiomyocyte-specific Pcbp1 knockout and Aars2 exon-16 skipping mutant mice with splicing, proteomic, OXPHOS, and UPR readouts","pmids":["42010330","37293078"],"confidence":"Medium","gaps":["Single lab","Mechanism of PCBP1 splice-site selection on Aars2 not detailed"]},{"year":2024,"claim":"Redefined AARS2 as a moonlighting L-lactate sensor and lactyltransferase, establishing that it inactivates cGAS by lactylation to suppress DNA sensing — a function distinct from its synthetase activity.","evidence":"Biochemical binding assays, in vitro lactylation reconstitution, Co-IP, genetic code expansion, lactyl-mimetic/resistant knock-in mice, phase separation assays","pmids":["39322678"],"confidence":"High","gaps":["Full substrate spectrum of the lactyltransferase activity not defined","Relationship between aminoacylation and lactyltransferase active sites not resolved"]},{"year":2025,"claim":"Connected AARS2 lactyltransferase activity to metabolic enzyme regulation in reproduction, showing lactylation of CPT2 and PDHA1 reprograms granulosa cell metabolism to drive folliculogenesis and ovarian insufficiency.","evidence":"In vitro lactylation assays on CPT2/PDHA1, GC-specific overexpression and knockout mice, metabolic measurements","pmids":["40301335"],"confidence":"Medium","gaps":["Single lab","Site-specific lactylation mapping on CPT2/PDHA1 not fully resolved"]},{"year":2025,"claim":"Identified a translation-regulatory role for AARS2 in the heart, showing it promotes PKM2 translation to shift cardiomyocytes toward glycolysis and protect against apoptosis and fibrosis.","evidence":"Cardiomyocyte-specific Aars2 deletion/overexpression mice, Ribo-Seq, PKM2 dimer/tetramer assays, TEPP-46 rescue","pmids":["40371904"],"confidence":"Medium","gaps":["Mechanism by which AARS2 engages ribosomes to favor PKM2 translation not defined","Single lab"]},{"year":2026,"claim":"Linked the AARS2 R194C/R199C pathogenic variant to gain of lactyltransferase function in vivo, showing increased PDHA1/CPT2 lactylation impairs respiration and activates mTORC1 to cause premature ovarian insufficiency, reversible by SIRT3.","evidence":"Homozygous Aars2 R194C knock-in mice, lactylation and respiration assays, mTORC1 analysis, pharmacological PDHA1/CPT2 inhibition rescue","pmids":["41832996"],"confidence":"Medium","gaps":["Single lab, no independent replication","SIRT3-AARS2 regulatory balance not fully characterized"]},{"year":2026,"claim":"Extended AARS2 lactyltransferase function to oncogenic signaling, showing site-specific lactylation of AP-2γ at K444 promotes its stabilization and tumor progression while suppressing cGAS-STING immune output.","evidence":"MS identification of K444 lactylation, AP-2γ-TRIM28 Co-IP, ubiquitination assays, AARS2 knockdown with lactate and immune gene readouts","pmids":["42114979"],"confidence":"Medium","gaps":["Single lab","Direct contribution of AARS2 catalysis versus lactate supply to AP-2γ lactylation in vivo not separated"]},{"year":null,"claim":"How AARS2 partitions between its canonical mitochondrial aminoacylation function and its lactyltransferase activity, and what determines its substrate selectivity across tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model reconciling aminoacylation and lactyltransferase active sites","Tissue-specific substrate selection rules unknown","Subcellular distribution governing access to nuclear/cytosolic substrates not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5,6]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8]}],"complexes":[],"partners":["CGAS","CPT2","PDHA1","PKM2","AP-2Γ","TRIM28","PCBP1","SIRT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5JTZ9","full_name":"Alanine--tRNA ligase, mitochondrial","aliases":["Alanyl-tRNA synthetase","AlaRS","Protein lactyltransferase AARS2"],"length_aa":985,"mass_kda":107.3,"function":"Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain (PubMed:21549344). In presence of high levels of lactate, also acts as a protein lactyltransferase that mediates lactylation of lysine residues in target proteins, such as CGAS (PubMed:39322678). Acts as an inhibitor of cGAS/STING signaling by catalyzing lactylation of CGAS, preventing the formation of liquid-like droplets in which CGAS is activated (PubMed:39322678)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q5JTZ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/AARS2","classification":"Common Essential","n_dependent_lines":728,"n_total_lines":1208,"dependency_fraction":0.6026490066225165},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AARS2","total_profiled":1310},"omim":[{"mim_id":"620788","title":"HIG1 HYPOXIA-INDUCIBLE DOMAIN FAMILY, MEMBER 2A; HIGD2A","url":"https://www.omim.org/entry/620788"},{"mim_id":"615889","title":"LEUKOENCEPHALOPATHY, PROGRESSIVE, WITH OVARIAN FAILURE; LKENP","url":"https://www.omim.org/entry/615889"},{"mim_id":"614096","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 8; COXPD8","url":"https://www.omim.org/entry/614096"},{"mim_id":"612035","title":"ALANYL-tRNA SYNTHETASE 2; AARS2","url":"https://www.omim.org/entry/612035"},{"mim_id":"609060","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 1; COXPD1","url":"https://www.omim.org/entry/609060"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AARS2"},"hgnc":{"alias_symbol":["KIAA1270","bA444E17.1"],"prev_symbol":["AARSL"]},"alphafold":{"accession":"Q5JTZ9","domains":[{"cath_id":"3.30.930.10","chopping":"40-286","consensus_level":"medium","plddt":91.6681,"start":40,"end":286},{"cath_id":"-","chopping":"290-415","consensus_level":"medium","plddt":89.3783,"start":290,"end":415},{"cath_id":"2.40.30.130","chopping":"497-520_533-620","consensus_level":"high","plddt":90.3258,"start":497,"end":620},{"cath_id":"3.30.980.10","chopping":"622-693_757-878","consensus_level":"medium","plddt":92.6764,"start":622,"end":878},{"cath_id":"3.10.310.40","chopping":"880-985","consensus_level":"high","plddt":91.6362,"start":880,"end":985},{"cath_id":"1.10.10","chopping":"427-487","consensus_level":"medium","plddt":71.7461,"start":427,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JTZ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JTZ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JTZ9-F1-predicted_aligned_error_v6.png","plddt_mean":87.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AARS2","jax_strain_url":"https://www.jax.org/strain/search?query=AARS2"},"sequence":{"accession":"Q5JTZ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5JTZ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5JTZ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JTZ9"}},"corpus_meta":[{"pmid":"39322678","id":"PMC_39322678","title":"AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39322678","citation_count":277,"is_preprint":false},{"pmid":"27749956","id":"PMC_27749956","title":"Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia.","date":"2016","source":"JAMA neurology","url":"https://pubmed.ncbi.nlm.nih.gov/27749956","citation_count":80,"is_preprint":false},{"pmid":"28243630","id":"PMC_28243630","title":"Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy.","date":"2017","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28243630","citation_count":65,"is_preprint":false},{"pmid":"25705216","id":"PMC_25705216","title":"Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation.","date":"2015","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25705216","citation_count":51,"is_preprint":false},{"pmid":"27251004","id":"PMC_27251004","title":"The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations.","date":"2016","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27251004","citation_count":31,"is_preprint":false},{"pmid":"27734837","id":"PMC_27734837","title":"Novel AARS2 gene mutation producing leukodystrophy: a case report.","date":"2016","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27734837","citation_count":27,"is_preprint":false},{"pmid":"31099476","id":"PMC_31099476","title":"Expansion of the clinical spectrum associated with AARS2-related disorders.","date":"2019","source":"American journal of medical genetics. 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c.334 G > C, p.G112R) identified in a Chinese patient with leukodystrophy involved in brain and spinal cord.","date":"2019","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31388113","citation_count":3,"is_preprint":false},{"pmid":"38507676","id":"PMC_38507676","title":"Pearls & Oy-sters: AARS2 Leukodystrophy-Tremor and Tribulations.","date":"2024","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38507676","citation_count":1,"is_preprint":false},{"pmid":"42010330","id":"PMC_42010330","title":"PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.","date":"2026","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/42010330","citation_count":1,"is_preprint":false},{"pmid":"37456626","id":"PMC_37456626","title":"Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37456626","citation_count":1,"is_preprint":false},{"pmid":"35676634","id":"PMC_35676634","title":"Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy.","date":"2022","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35676634","citation_count":1,"is_preprint":false},{"pmid":"39853526","id":"PMC_39853526","title":"Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy.","date":"2025","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/39853526","citation_count":0,"is_preprint":false},{"pmid":"41836446","id":"PMC_41836446","title":"Integrative pan-cancer analysis reveals AARS2 as a lactylation-associated biomarker and therapeutic target in colon adenocarcinoma.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41836446","citation_count":0,"is_preprint":false},{"pmid":"42114979","id":"PMC_42114979","title":"Landscape screening identifies the lactate-modifying enzyme AARS2 as a master regulator and therapeutic target in hepatocellular carcinoma.","date":"2026","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/42114979","citation_count":0,"is_preprint":false},{"pmid":"41832996","id":"PMC_41832996","title":"AARS2 R199C mutation induces lactylation-driven premature ovarian insufficiency phenotypes partially reversible by SIRT3.","date":"2026","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41832996","citation_count":0,"is_preprint":false},{"pmid":"39539319","id":"PMC_39539319","title":"A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy - A case report.","date":"2024","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/39539319","citation_count":0,"is_preprint":false},{"pmid":"35975211","id":"PMC_35975211","title":"Gait Apraxia with Exaggerated Upper Limb Movements as Presentation of AARS2 Related Leukoencephalopathy.","date":"2022","source":"Tremor and other hyperkinetic movements (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35975211","citation_count":0,"is_preprint":false},{"pmid":"40688999","id":"PMC_40688999","title":"Expanding the Phenotype: A Case Report of a Novel Alanyl-tRNA Synthetase 2 (AARS2) Homozygous Mutation in a 17-Month-Old Child.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/40688999","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19024,"output_tokens":2776,"usd":0.049356,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10080,"output_tokens":3455,"usd":0.068388,"stage2_stop_reason":"end_turn"},"total_usd":0.117744,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"AARS2 (and AARS1) directly bind L-lactate with micromolar affinity and catalyze ATP-dependent lysine lactylation, functioning as intracellular L-lactate sensors and lactyltransferases. In response to elevated L-lactate, AARS2 associates with cGAS and mediates its lactylation and inactivation in cells and in mice, abolishing cGAS liquid-like phase separation and DNA sensing.\",\n      \"method\": \"Biochemical binding assays, in vitro lactylation reconstitution, Co-IP (AARS2–cGAS association), genetic code expansion orthogonal system for lactyl-lysine incorporation, lactyl-mimetic and lactyl-resistant knock-in mouse models, in vitro and in vivo phase separation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of lactylation activity, mutagenesis via knock-in models, multiple orthogonal methods (binding assays, Co-IP, cell-based, in vivo), replicated across cells and mice\",\n      \"pmids\": [\"39322678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AARS2 lactylates and inactivates carnitine palmitoyl transferase 2 (CPT2), resulting in free fatty acid accumulation that activates PPARγ and potentiates FSH-driven follicle development. AARS2 also promotes PDHA1 inactivation via lactylation, stimulating granulosa cell proliferation and primordial follicle development. GC-specific AARS2 overexpression accelerates follicle depletion, while AARS2 ablation or β-alanine treatment prevents folliculogenesis and POI traits in mice.\",\n      \"method\": \"AARS2 gain-of-function mutation characterization, in vitro lactylation assays on CPT2 and PDHA1, GC-specific AARS2 overexpression and knockout mouse models, metabolic measurements (FFA, PPARγ activation)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct lactylation assays on substrates combined with in vivo mouse models, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40301335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a homozygous Aars2 R194C knock-in mouse model (mimicking human R199C pathogenic variant), the mutation increases lysine lactylation of PDHA1 and CPT2, reduces their activity, impairs mitochondrial respiration in granulosa cells, activates mTORC1 signaling, and causes premature follicle activation and POI. SIRT3 (mitochondrial de-lactylase) loss mitigated these abnormalities; pharmacological inhibition of PDHA1/CPT2 in WT mice phenocopied the knock-in.\",\n      \"method\": \"Homozygous knock-in mouse model, lysine lactylation measurements on endogenous substrates, mitochondrial respiration assays, mTORC1 pathway analysis, pharmacological inhibition rescue experiments\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in model with multiple orthogonal functional assays, single lab, no independent replication yet\",\n      \"pmids\": [\"41832996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AARS2 overexpression in cardiomyocytes suppresses apoptosis and mitochondrial ROS production and shifts cellular metabolism from oxidative phosphorylation toward glycolysis. Ribosome profiling (Ribo-Seq) revealed that Aars2 overexpression increases PKM2 protein translation and promotes the PKM2 dimer-to-tetramer ratio favoring glycolysis. PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency, defining an AARS2–PKM2 signaling axis.\",\n      \"method\": \"Cardiomyocyte-specific Aars2 deletion and overexpression mouse models, Ribo-Seq (translational profiling), PKM2 dimer/tetramer ratio assays, pharmacological rescue with TEPP-46, cardiac function measurements\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including Ribo-Seq and genetic/pharmacological rescue, single lab\",\n      \"pmids\": [\"40371904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 interacts with the Aars2 transcript to mediate its alternative splicing in cardiomyocytes. Cardiomyocyte-specific deletion of Pcbp1 causes aberrant alternative splicing and premature termination of Aars2, reducing oxidative phosphorylation and triggering mitonuclear communication and the unfolded protein response. Aars2 mutant mice with exon-16 skipping recapitulate heart developmental defects, and loss of Pcbp1 or Aars2 reduces the mitochondrial-encoded proteome.\",\n      \"method\": \"Cardiomyocyte-specific Pcbp1 knockout mice, Aars2 exon-16 skipping mutant mice, RNA splicing analysis, oxidative phosphorylation measurements, proteomics of mitochondrial-encoded proteins, UPR pathway analysis\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models with multiple orthogonal readouts (splicing, proteomics, OXPHOS), single lab, peer-reviewed publication\",\n      \"pmids\": [\"42010330\", \"37293078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Structural modeling of AARS2 predicts that the cardiomyopathy-causing R592W mutation resides in the editing domain responsible for deacylating mischarged tRNAs, while leukodystrophy mutations affect other domains; all mutations are predicted to reduce aminoacylation activity because all AARS2 domains contribute to tRNA binding. The cardiomyopathy allele is predicted to severely compromise aminoacylation, whereas leukodystrophy allele combinations retain partial activity.\",\n      \"method\": \"Structural homology modeling of AARS2 domains, mapping of disease mutations onto predicted 3D structure\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural modeling only, no experimental biochemical validation reported in the abstract\",\n      \"pmids\": [\"25705216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous AARS2 mutation (p.G113R) in the aminoacylation domain significantly reduced ATP production in patient-derived cells compared to wild-type (3.58 vs 6.96 fmol/min/cell), consistent with impaired mitochondrial translation due to defective aminoacylation of tRNA-Ala.\",\n      \"method\": \"Seahorse XFe96 metabolic analyzer measuring oxygen consumption, ATP production, and extracellular acidification rate in patient cells carrying the AARS2 mutation vs. wild-type\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional metabolic assay in patient-derived cells, single lab, single method\",\n      \"pmids\": [\"31280959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yeast complementation assays demonstrated that the AARS2 p.Phe131del variant dramatically impairs AARS2 gene function, while p.Ile328Met is a hypomorphic allele, establishing that these variants cause loss of AARS2 function sufficient to produce ataxia without leukoencephalopathy.\",\n      \"method\": \"Yeast complementation assay using AARS2 variants (p.Phe131del and p.Ile328Met)\",\n      \"journal\": \"Cerebellum (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional complementation assay in model organism, single lab, single method, directly tests variant activity\",\n      \"pmids\": [\"31705293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AARS2 catalyzes lactylation of AP-2γ at K444, enhancing TRIM28 binding and promoting K63-linked ubiquitination and nuclear translocation of AP-2γ to facilitate HCC tumor progression. AARS2 knockdown in HCT116 colon cancer cells reduced extracellular lactate accumulation and attenuated global protein lactylation, and upregulated cGAS-STING pathway genes (CCL5, CXCL10, IFNB1).\",\n      \"method\": \"Mass spectrometry identification of lactylation site on AP-2γ (K444), Co-IP of AP-2γ–TRIM28, ubiquitination assays, AARS2 knockdown in cancer cell lines, extracellular lactate measurement, qRT-PCR of immune genes\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific lactylation identified by MS, Co-IP interaction, functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"42114979\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AARS2 is a mitochondrial alanyl-tRNA synthetase that charges tRNA-Ala with alanine to support mitochondrial protein synthesis, but it also functions as an intracellular L-lactate sensor and lactyltransferase: it binds L-lactate with micromolar affinity and catalyzes ATP-dependent lysine lactylation of substrates including cGAS (suppressing innate immune signaling), CPT2 and PDHA1 (impairing mitochondrial metabolism to drive premature ovarian insufficiency), and AP-2γ (promoting oncogenic signaling); in the heart, AARS2 additionally regulates PKM2 protein translation via ribosome engagement to shift cardiomyocyte metabolism toward glycolysis under ischemic stress, and its cardiac-specific splicing is controlled by the RNA-binding protein PCBP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AARS2 is a mitochondrial alanyl-tRNA synthetase whose aminoacylation activity supports mitochondrial protein synthesis, and which additionally functions as an intracellular L-lactate sensor and lactyltransferase [#0, #6]. AARS2 binds L-lactate with micromolar affinity and catalyzes ATP-dependent lysine lactylation of target proteins; acting on cGAS, it lactylates and inactivates the sensor, abolishing its phase separation and DNA-sensing activity to suppress innate immune signaling [#0]. Through lactylation of metabolic enzymes CPT2 and PDHA1, AARS2 inactivates both, driving free fatty acid accumulation, PPARγ activation, impaired mitochondrial respiration, mTORC1 activation, and premature follicle activation that underlies premature ovarian insufficiency; the de-lactylase SIRT3 opposes these effects [#1, #2]. In cancer, AARS2 lactylates AP-2γ at K444 to enhance TRIM28 binding, K63-linked ubiquitination, and nuclear translocation, promoting tumor progression while restraining cGAS-STING immune gene expression [#8]. In the heart, AARS2 increases PKM2 translation and shifts cardiomyocyte metabolism toward glycolysis to limit apoptosis and ROS under stress, defining an AARS2-PKM2 axis [#3], and its cardiomyocyte splicing is controlled by the RNA-binding protein PCBP1, with aberrant splicing reducing oxidative phosphorylation and the mitochondrial-encoded proteome [#4]. Disease-associated AARS2 mutations compromise aminoacylation activity, reducing ATP production in patient cells and producing loss of function in complementation assays, linking AARS2 to cardiomyopathy, leukodystrophy, and ataxia phenotypes [#5, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established how disease mutations map onto AARS2 functional domains, framing the synthetase's aminoacylation and editing activities as the basis for genotype-phenotype differences in cardiomyopathy versus leukodystrophy.\",\n      \"evidence\": \"Structural homology modeling mapping disease mutations onto predicted 3D domains\",\n      \"pmids\": [\"25705216\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational modeling only, no experimental biochemical validation of predicted activity\", \"Domain contributions to tRNA binding not directly measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated functionally that an aminoacylation-domain mutation impairs mitochondrial energy output, confirming AARS2 loss of function reduces ATP production via defective tRNA-Ala charging.\",\n      \"evidence\": \"Seahorse metabolic analysis of patient-derived cells versus wild-type\",\n      \"pmids\": [\"31280959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method, single mutation\", \"Direct measurement of aminoacylation activity not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed pathogenicity and severity ranking of specific AARS2 variants, establishing thresholds of lost function sufficient to produce ataxia without leukoencephalopathy.\",\n      \"evidence\": \"Yeast complementation assay with p.Phe131del and p.Ile328Met variants\",\n      \"pmids\": [\"31705293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single assay in heterologous system\", \"Mechanistic link to neuronal phenotype not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an upstream regulatory layer controlling cardiac AARS2 expression, showing PCBP1-mediated alternative splicing is required for proper Aars2 transcript processing and mitochondrial translation in the heart.\",\n      \"evidence\": \"Cardiomyocyte-specific Pcbp1 knockout and Aars2 exon-16 skipping mutant mice with splicing, proteomic, OXPHOS, and UPR readouts\",\n      \"pmids\": [\"42010330\", \"37293078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of PCBP1 splice-site selection on Aars2 not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Redefined AARS2 as a moonlighting L-lactate sensor and lactyltransferase, establishing that it inactivates cGAS by lactylation to suppress DNA sensing — a function distinct from its synthetase activity.\",\n      \"evidence\": \"Biochemical binding assays, in vitro lactylation reconstitution, Co-IP, genetic code expansion, lactyl-mimetic/resistant knock-in mice, phase separation assays\",\n      \"pmids\": [\"39322678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate spectrum of the lactyltransferase activity not defined\", \"Relationship between aminoacylation and lactyltransferase active sites not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected AARS2 lactyltransferase activity to metabolic enzyme regulation in reproduction, showing lactylation of CPT2 and PDHA1 reprograms granulosa cell metabolism to drive folliculogenesis and ovarian insufficiency.\",\n      \"evidence\": \"In vitro lactylation assays on CPT2/PDHA1, GC-specific overexpression and knockout mice, metabolic measurements\",\n      \"pmids\": [\"40301335\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Site-specific lactylation mapping on CPT2/PDHA1 not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a translation-regulatory role for AARS2 in the heart, showing it promotes PKM2 translation to shift cardiomyocytes toward glycolysis and protect against apoptosis and fibrosis.\",\n      \"evidence\": \"Cardiomyocyte-specific Aars2 deletion/overexpression mice, Ribo-Seq, PKM2 dimer/tetramer assays, TEPP-46 rescue\",\n      \"pmids\": [\"40371904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AARS2 engages ribosomes to favor PKM2 translation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked the AARS2 R194C/R199C pathogenic variant to gain of lactyltransferase function in vivo, showing increased PDHA1/CPT2 lactylation impairs respiration and activates mTORC1 to cause premature ovarian insufficiency, reversible by SIRT3.\",\n      \"evidence\": \"Homozygous Aars2 R194C knock-in mice, lactylation and respiration assays, mTORC1 analysis, pharmacological PDHA1/CPT2 inhibition rescue\",\n      \"pmids\": [\"41832996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no independent replication\", \"SIRT3-AARS2 regulatory balance not fully characterized\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended AARS2 lactyltransferase function to oncogenic signaling, showing site-specific lactylation of AP-2γ at K444 promotes its stabilization and tumor progression while suppressing cGAS-STING immune output.\",\n      \"evidence\": \"MS identification of K444 lactylation, AP-2γ-TRIM28 Co-IP, ubiquitination assays, AARS2 knockdown with lactate and immune gene readouts\",\n      \"pmids\": [\"42114979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct contribution of AARS2 catalysis versus lactate supply to AP-2γ lactylation in vivo not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AARS2 partitions between its canonical mitochondrial aminoacylation function and its lactyltransferase activity, and what determines its substrate selectivity across tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model reconciling aminoacylation and lactyltransferase active sites\", \"Tissue-specific substrate selection rules unknown\", \"Subcellular distribution governing access to nuclear/cytosolic substrates not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"cGAS\", \"CPT2\", \"PDHA1\", \"PKM2\", \"AP-2γ\", \"TRIM28\", \"PCBP1\", \"SIRT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}