Advertisement

ResearchIn-Press PreviewCell biologyMetabolism Open Access | 10.1172/JCI190215

Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase

Chao-Chieh Lin,1 Yi-Tzu Lin,1 Ssu-Yu Chen,1 Yasaman Setayeshpour,1 Yubin Chen,1 Denise E. Dunn,2 Taylor Nguyen,2 Alexander A. Mestre,1 Adrija Banerjee,3 Lalitha Guruprasad,3 Erik J. Soderblom,4 Guo-Fang Zhang,5 Chen-Yong Lin,6 Valeriy Filonenko,7 Suh Young Jeong,8 Scott R. Floyd,2 Susan J. Hayflick,8 Ivan Gout,7 and Jen-Tsan Chi1

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Lin, C. in: PubMed | Google Scholar |

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Lin, Y. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Chen, S. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Setayeshpour, Y. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Chen, Y. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Dunn, D. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Nguyen, T. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Mestre, A. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Banerjee, A. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Guruprasad, L. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Soderblom, E. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Zhang, G. in: PubMed | Google Scholar |

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Lin, C. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Filonenko, V. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Jeong, S. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Floyd, S. in: PubMed | Google Scholar |

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Hayflick, S. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Gout, I. in: PubMed | Google Scholar

1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America

2Department of Radiation Oncology, Duke University School of Medicine, Durham, United States of America

3School of Chemistry, University of Hyderabad, Hyderabad, India

4Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, United States of America

5Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Meta, Duke University School of Medicine, Durham, United States of America

6Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, United States of America

7Department of Cell Signaling, nstitute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine

8Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, United States of America

Find articles by Chi, J. in: PubMed | Google Scholar |

Published July 22, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190215.
Copyright © 2025, Lin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 22, 2025 - Version history
View PDF
Abstract

The cystine-xCT transporter–glutathione (GSH)–GPX4 axis is the canonical pathway protecting cells from ferroptosis. While GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Since 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 (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 demonstrated 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 post-translational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (July 22, 2025): In-Press Preview
Advertisement
Advertisement