ArticleCell2014
Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.
Article in Cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 253 papers.
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Who cites it
253 citing papers in PubMed, 424 citations in OpenAlex.
- Rhynchophylline rewires DLAT lipoylationActa pharmaceutica Sinica. B · 2026Article
- Comparative Structure-Based Analysis of Predicted BZD9L1 Binding Modes Across Human Sirtuins.International journal of molecular sciences · 2026Article
- The Sirtuin Network: Linking NADDiabetes/metabolism research and reviews · 2026Review
- Targeting Sirtuins in Thyroid Cancer: Mechanisms, Drug Development, and Emerging Roles in Tumor Immunity and Ferroptosis.Cancers · 2026Review
- Sirtuins at the Interface of Glucose Metabolism, Diabetes, and Heart Failure: Metabolic Sensing in Cardiometabolic Disease.International journal of molecular sciences · 2026Review
- Mechanistic and functional integration of sirtuin deacylases: from substrate specificity to biological outcomes.Glycoconjugate journal · 2026Review
- Cuproptosis causes meiotic metaphase I arrest by disrupting mitochondrial functions in oocytes.Cell death discovery · 2026Article
- Beyond deacetylation: crosstalk mechanisms and context-dependent regulation of sirtuin non-classical enzymatic functions in disease.Molecular medicine (Cambridge, Mass.) · 2026Review
- SIRT4 positively regulates autophagy via ULK1, but independently of HDAC6 and OPA1.FEBS open bio · 2026Article
- SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington's disease models.Cell communication and signaling : CCS · 2026Article
- Molecular mechanisms underlying Parkinson's disease and role of phytochemicals, α-synuclein, sirtuins, and incretin mimetics in potential therapy.Frontiers in pharmacology · 2026Review
- Targeting multiple genetic defects of mitochondrial diseases with a single bacterial lipoate protein ligase.Science advances · 2025Article
- Isoform-specific regulation of PKM by acetylation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.Nature chemical biology · 2025Article
- A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in gastric cancer.Nature communications · 2025Article
- Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Article
- Structural basis of SIRT2 pre-catalysis NADRSC chemical biology · 2025Article
- Mitochondrial Dynamics in Aging Heart.Biomedicines · 2025Review
- Protein lipoylation in cancer: metabolic reprogramming and therapeutic potential.Cell death discovery · 2025Review
193 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism.
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Registered trials
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.