Cytosolic cytochrome c represses ferroptosis

  • Cell Metab. 2025 Apr 8:S1550-4131(25)00149-4. doi: 10.1016/j.cmet.2025.03.014.
Xinxin Song  1 ,  Zhuan Zhou  1 ,  Jiao Liu  2 ,  Jingbo Li  1 ,  Chunhua Yu  1 ,  Herbert J Zeh  1 ,  Daniel J Klionsky  3 ,  Brent R Stockwell  4 ,  Jiayi Wang  5 ,  Rui Kang  6 ,  Guido Kroemer  7 ,  Daolin Tang  8
Affiliations
  • 1. Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Department of Critical Care Medicine, State Key Laboratory of Respiratory Disease, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China.
  • 3. Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 4. Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA.
  • 5. Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 6. Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
  • 7. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France. Electronic address: [email protected].
  • 8. Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 40233758 DOI: 10.1016/j.cmet.2025.03.014
Abstract

The release of cytochrome c, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent Apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis-a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial Apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to Ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.

Keywords
apoptosis; cytochrome c; ferroptosis; protein complex.
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