ArticleCell research2024
Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation.
Article in Cell research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 258 papers.
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Who cites it
258 citing papers in PubMed, 248 citations in OpenAlex.
- Lactylation and exercise: A molecular link to disease alleviation (Review).Molecular medicine reports · 2026Review
- Metabolic memory in the kidney: how lactate and lactylation drive the path from acute injury to chronic disease.Renal failure · 2026Review
- Levofloxacin enhances 5-fluorouracil efficacy in colorectal cancer by activating the DDR-TP53-mitochondrial apoptosis axis.iScience · 2026Article
- Exercise-induced protein lactylation: From molecular mechanisms to precision health applications.iScience · 2026Review
- Regulation of PDH via cysteine oxidation on DLAT.Nature communications · 2026Article
- Lactate Signal: Modulator of Cellular Energy Production and Anabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- CD112 Lactylation Drives Dual Immune Evasion From CD8+ T Cells and NK Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lysine pyruvylation: decoding the molecular language of pyruvate signaling.EMBO molecular medicine · 2026Article
- Lactylation-dependent DDX18 nucleolar escape regulates CD44 mRNA stability to drive fibrotic progression in kidney injury.The Journal of clinical investigation · 2026Article
- Unveiling the "Glycolysis-Lactate-Lactylation" Axis: A Novel Target in Ischemic Cerebrovascular Disease.Neuroscience bulletin · 2026Review
- AARS2-SIRT5-Driven DLD K445 Lactylation Promotes Cuproptosis Resistance in Glioblastoma Stem Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Fumarate Hydratase Lactylation Exacerbates Traumatic Brain Injury Pathology via Mitochondrial Dysfunction and Neuroinflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response.Current issues in molecular biology · 2026Review
- KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.Cell death and differentiation · 2026Article
- Infection and α-ketoglutarate/oxygen inhibition converge to CDC20 to promote cancer cell aneuploidy.Signal transduction and targeted therapy · 2026Article
- Redox coupling of lactate and β-hydroxybutyrate: An inter-organ circuit linking metabolic flexibility, mitochondrial adaptation, and disease.Redox biology · 2026Review
- Lactylation Modification and Esophageal Cancer: Research Progress From Hypoxia-Induced Metabolic Reprogramming to Immune Escape.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- The Trajectory of Epigenetic Chromatin Remodeling in Cardiometabolic Disease and its Therapeutic Implications.Journal of cardiovascular translational research · 2026Review
- Identifying causal genetic variants for high-altitude adaptation through blood eQTL analysis in plateau populations.Communications biology · 2026Article
- Article
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17 authors at 6 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.