Repression of ferroptotic cell death by mitochondrial calcium signaling

Jianwen Chen; Bao Zhao; Shen Wang; Anjun Ma; Hong Dong; Xiang Cheng; Shengyin Lin; Xinghui Li; Laura E Herring; Gang Xin; Qin Ma; Kai He; Ruili Xie; Yu L Lei; Irina Ingold; Xiaolin Cheng; Zihai Li; Haitao Wen

doi:10.21203/rs.3.rs-3029860/v1

Repression of ferroptotic cell death by mitochondrial calcium signaling

Res Sq [Preprint]. 2023 Jul 10:rs.3.rs-3029860. doi: 10.21203/rs.3.rs-3029860/v1.

Authors

Jianwen Chen^{1

2

3}, Bao Zhao^{1

2

3}, Shen Wang⁴, Anjun Ma^{2

5}, Hong Dong¹, Xiang Cheng^{1

2}, Shengyin Lin^{6

7}, Xinghui Li^{1

8}, Laura E Herring⁹, Gang Xin^{1

2}, Qin Ma^{2

5}, Kai He^{2

10}, Ruili Xie^{6

7}, Yu L Lei¹¹, Irina Ingold¹², Xiaolin Cheng^{4

13}, Zihai Li², Haitao Wen^{1

2}

Affiliations

¹ Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, OH, USA.
² Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
³ These authors are equally to this work.
⁴ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
⁵ Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
⁶ Department of Otolaryngology-Head and Neck Surgery, The Ohio State University, Columbus, OH, USA.
⁷ Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
⁸ Present Address: Bioanalytic Laboratories, Medpace Holdings, Inc., Cincinnati, OH, USA.
⁹ Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, OH, USA.
¹¹ Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48105, USA.
¹² Department of Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
¹³ Translational Data Analytics Institute (TDAI), The Ohio State University, Columbus, OH, USA.

Abstract

The uptake of Ca²⁺ into and extrusion of calcium from the mitochondrial matrix, regulated by the mitochondrial Ca²⁺ uniporter (MCU), is a fundamental biological process that has crucial impacts on cellular metabolism, signaling, growth and survival. Herein, we report that the embryonic lethality of Mcu-deficient mice is fully rescued by orally supplementing ferroptosis inhibitor lipophilic antioxidant vitamin E and ubiquinol. Mechanistically, we found MCU promotes acetyl-CoA-mediated GPX4 acetylation at K90 residue, and K90R mutation impaired the GPX4 enzymatic activity, a step that is crucial for ferroptosis. Structural analysis supports the possibility that GPX4 K90R mutation alters the conformational state of the molecule, resulting in disruption of a salt bridge formation with D23, which was confirmed by mutagenesis studies. Finally, we report that deletion of MCU in cancer cells caused a marked reduction in tumor growth in multiple cancer models. In summary, our study provides a first direct link between mitochondrial calcium level and sustained GPX4 enzymatic activity to regulate ferroptosis, which consequently protects cancer cells from ferroptosis.

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Abstract

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