2. Academic Validation
  3. Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase

Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase

  • J Clin Invest. 2025 Jul 22;135(19):e190215. doi: 10.1172/JCI190215.
Chao-Chieh Lin 1 2,  Yi-Tzu Lin 1 2,  Ssu-Yu Chen 1 2,  Yasaman Setayeshpour 1 2,  Yubin Chen 1 2,  Denise E Dunn 3,  Taylor Nguyen 3,  Alexander A Mestre 1 2 4,  Adrija Banerjee 5,  Lalitha Guruprasad 5,  Erik J Soderblom 6,  Guo-Fang Zhang 7 8,  Chen-Yong Lin 9,  Valeriy Filonenko 10,  Suh Young Jeong 11,  Scott R Floyd 3,  Susan J Hayflick 11 12,  Ivan Gout 10 13,  Jen-Tsan Chi 1 2
Affiliations

Affiliations

  • 1 Department of Molecular Genetics and Microbiology.
  • 2 Duke Center for Genomic and Computational Biology.
  • 3 Department of Radiation Oncology, and.
  • 4 Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina, USA.
  • 5 School of Chemistry, University of Hyderabad, Hyderabad, India.
  • 6 Proteomics and Metabolomics Core Facility.
  • 7 Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, and.
  • 8 Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, North Carolina, USA.
  • 9 Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, DC, USA.
  • 10 Department of Cell Signaling, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
  • 11 Department of Molecular & Medical Genetics.
  • 12 Pediatrics, and Neurology, Oregon Health & Science University, Portland, Oregon, USA.
  • 13 Department of Structural and Molecular Biology, University College London, London, United Kingdom.
PMID: 40694424 DOI: 10.1172/JCI190215
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.

Keywords

Amino acid metabolism; Cell biology; Cell stress; Metabolism; Mitochondria.

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