PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Zhiyi Chen; Alex Inague; Kamini Kaushal; Gholamreza Fazeli; Danny Schilling; Thamara N Xavier da Silva; Ancely Ferreira Dos Santos; Tasneem Cheytan; Florencio Porto Freitas; Umut Yildiz; Lucas Gasparello Viviani; Rodrigo Santiago Lima; Mikaela Peglow Pinz; Isadora Medeiros; Thais Satie Iijima; Thiago Geronimo Pires Alegria; Railmara Pereira da Silva; Larissa Regina Diniz; Simon Weinzweig; Judith Klein-Seetharaman; Andreas Trumpp; Adriana Mañas; Robert Hondal; Christoph Bartenhagen; Matthias Fischer; Briana K Shimada; Lucia A Seale; Thilo Samson Chillon; Marietta Fabiano; Lutz Schomburg; Ulrich Schweizer; Luis E Netto; Flavia C Meotti; Tobias P Dick; Hamed Alborzinia; Sayuri Miyamoto; José Pedro Friedmann Angeli

doi:10.1016/j.molcel.2024.10.027

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Mol Cell. 2024 Nov 7:S1097-2765(24)00867-0. doi: 10.1016/j.molcel.2024.10.027. Online ahead of print.

Authors

Zhiyi Chen¹, Alex Inague², Kamini Kaushal³, Gholamreza Fazeli¹, Danny Schilling⁴, Thamara N Xavier da Silva¹, Ancely Ferreira Dos Santos¹, Tasneem Cheytan³, Florencio Porto Freitas¹, Umut Yildiz⁵, Lucas Gasparello Viviani⁶, Rodrigo Santiago Lima⁶, Mikaela Peglow Pinz⁶, Isadora Medeiros⁶, Thais Satie Iijima⁶, Thiago Geronimo Pires Alegria⁷, Railmara Pereira da Silva⁶, Larissa Regina Diniz⁶, Simon Weinzweig⁸, Judith Klein-Seetharaman⁸, Andreas Trumpp³, Adriana Mañas⁹, Robert Hondal¹⁰, Christoph Bartenhagen¹¹, Matthias Fischer¹¹, Briana K Shimada¹², Lucia A Seale¹², Thilo Samson Chillon¹³, Marietta Fabiano¹⁴, Lutz Schomburg¹³, Ulrich Schweizer¹⁴, Luis E Netto⁷, Flavia C Meotti⁶, Tobias P Dick⁴, Hamed Alborzinia¹⁵, Sayuri Miyamoto¹⁶, José Pedro Friedmann Angeli¹⁷

Affiliations

¹ Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Wuerzburg, 97080 Wuerzburg, Germany.
² Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Wuerzburg, 97080 Wuerzburg, Germany; Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508000 Sao Paulo, Brazil.
³ Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁴ Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵ European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
⁶ Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508000 Sao Paulo, Brazil.
⁷ Biosciences Institute, Department of Genetics and Evolutionary Biology, Universidade de São Paulo, 05508900 Sao Paulo, Brazil.
⁸ School of Molecular Sciences, Arizona State University, Phoenix, AZ 85281, USA.
⁹ Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Hospital Universitario La Paz, 28049 Madrid, Spain; IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28049 Madrid, Spain.
¹⁰ Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA.
¹¹ Center for Molecular Medicine Cologne (CMMC) and Department of Experimental Pediatric Oncology, University Children's Hospital, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
¹² Pacific Biosciences Research Center, University of Hawaii at Manoa, Honolulu, HI 96848, USA.
¹³ Institute for Experimental Endocrinology, CVK, Charité-Universtitätsmedizin Berlin, 10115 Berlin, Germany.
¹⁴ Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany.
¹⁵ Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: [email protected].
¹⁶ Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508000 Sao Paulo, Brazil. Electronic address: [email protected].
¹⁷ Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Wuerzburg, 97080 Wuerzburg, Germany. Electronic address: [email protected].

PMID: 39547224
DOI: 10.1016/j.molcel.2024.10.027

Abstract

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and begins with the uptake of the Sec carrier, selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP is metabolized via selenocysteine lyase (SCLY), producing selenide, a substrate for selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor, selenophosphate (H₂SePO₃^-), for the biosynthesis of the Sec-tRNA. Here, we discovered an alternative pathway in Sec metabolism mediated by peroxiredoxin 6 (PRDX6), independent of SCLY. Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.

Keywords: cancer metabolism; cell death; ferroptosis; neuroblastoma; selenium; selenocysteine metabolism.