Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase.
| Title: | Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase. |
|---|---|
| Authors: | Lin CC; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology.; Lin YT; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology.; Chen SY; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology.; Setayeshpour Y; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology.; Chen Y; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology.; Dunn DE; Department of Radiation Oncology, and.; Nguyen T; Department of Radiation Oncology, and.; Mestre AA; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology.; Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina, USA.; Banerjee A; School of Chemistry, University of Hyderabad, Hyderabad, India.; Guruprasad L; School of Chemistry, University of Hyderabad, Hyderabad, India.; Soderblom EJ; Proteomics and Metabolomics Core Facility.; Zhang GF; Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, and.; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, North Carolina, USA.; Lin CY; Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC, USA.; Filonenko V; Department of Cell Signaling, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.; Jeong SY; Department of Molecular & Medical Genetics.; Floyd SR; Department of Radiation Oncology, and.; Hayflick SJ; Department of Molecular & Medical Genetics.; Pediatrics, and Neurology, Oregon Health & Science University, Portland, Oregon, USA.; Gout I; Department of Cell Signaling, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.; Department of Structural and Molecular Biology, University College London, London, United Kingdom.; Chi JT; Department of Molecular Genetics and Microbiology.; Duke Center for Genomic and Computational Biology. |
| Source: | The Journal of clinical investigation [J Clin Invest] 2025 Jul 22; Vol. 135 (19). Date of Electronic Publication: 2025 Jul 22 (Print Publication: 2025). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: eCollection Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation; Original Publication: New Haven [etc.] American Society for Clinical Investigation. |
| MeSH Terms: | Ferroptosis*/drug effects ; Mitochondria*/enzymology ; Mitochondria*/genetics ; Coenzyme A*/metabolism ; Coenzyme A*/genetics ; Thioredoxin Reductase 2*/metabolism ; Thioredoxin Reductase 2*/genetics ; Mitochondrial Proteins*/metabolism ; Mitochondrial Proteins*/genetics; Fibroblasts/enzymology ; Amino Acid Transport System y+/metabolism ; Amino Acid Transport System y+/genetics ; Animals ; Humans ; Mice ; Lipid Peroxidation |
| Abstract: | The cystine-xCT transporter/glutathione/GPX4 axis is the canonical pathway protecting cells from ferroptosis. Whereas GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Because cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase-2 (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic activity and ability to protect cells against ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2. Furthermore, the fibroblasts from patients with disrupted CoA metabolism had increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis led to an oxidized thioredoxin system, increased mitochondrial lipid peroxidation, and loss of cell viability, which were all rescued by ferrostatin-1. These findings identified CoA-mediated posttranslational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism. |
| Comments: | Update of: Res Sq. 2024 Jun 18:rs.3.rs-4522617. doi: 10.21203/rs.3.rs-4522617/v1.. (PMID: 38947036) |
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| Grant Information: | R01 GM124062 United States GM NIGMS NIH HHS; R01 NS111588 United States NS NINDS NIH HHS; R21 AI149205 United States AI NIAID NIH HHS |
| Contributed Indexing: | Keywords: Amino acid metabolism; Cell biology; Cell stress; Metabolism; Mitochondria |
| Substance Nomenclature: | SAA04E81UX (Coenzyme A); EC 1.8.1.9 (Thioredoxin Reductase 2); EC 1.8.1.9 (TXNRD2 protein, human); 0 (Amino Acid Transport System y+); 0 (Mitochondrial Proteins) |
| Entry Date(s): | Date Created: 20250722 Date Completed: 20251001 Latest Revision: 20251003 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12483566 |
| DOI: | 10.1172/JCI190215 |
| PMID: | 40694424 |
| Database: | MEDLINE |
Journal Article