PRDX6 dictates ferroptosis sensitivity by directing cellular selenium mobilization DOI Open Access
Junya Ito, Toshitaka Nakamura, Takashi Toyama

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 5, 2024

Summary Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis and prevents unrestrained (phospho)lipid peroxidation by directly reducing phospholipid hydroperoxides (PLOOH) to their corresponding alcohols. However, it remains unclear whether other peroxidases can also contribute prevention, albeit a varying degree. Here we show that cells lacking GPX4 still exhibit substantial PLOOH reduction capacity, arguing for presence alternative peroxidases. By scrutinizing potential candidates, showed while overexpression peroxiredoxin 6 (PRDX6), thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed prevent ferroptosis, its genetic loss markedly sensitizes cancer ferroptosis. Mechanistically, uncover PRDX6 facilitates intracellular selenium handling, which crucial incorporation into selenoproteins, including GPX4. Consequently, modulates expression, thereby dictating sensitivity undergo Our study highlights as critical factor in prevention directing cellular mobilization.

Language: Английский

Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis DOI Open Access
Junichi Fujii, Hirotaka Imai

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7544 - 7544

Published: July 9, 2024

Ferroptosis is a type of nonapoptotic cell death that characteristically caused by phospholipid peroxidation promoted radical reactions involving iron. Researchers have identified many the protein factors are encoded genes promote ferroptosis. Glutathione peroxidase 4 (GPX4) key enzyme protects phospholipids from and suppresses ferroptosis in glutathione-dependent manner. Thus, dysregulation involved cysteine and/or glutathione metabolism closely associated with From perspective dynamics, actively proliferating cells more prone to than quiescent cells, which suggests species generated during oxygen-involved responsible for lipid peroxidation. Herein, we discuss initial events dominantly occur process energy metabolism, association deficiency. Accordingly, tricarboxylic acid cycle coupled respiratory chain mitochondria main subjects here, this likely source both electrons free Since not only carbohydrates, but also amino acids, especially glutamate, major substrates central dealing nitrogen derived groups contributes subject discussion.

Language: Английский

Citations

13
PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization DOI Creative Commons
Junya Ito, Toshitaka Nakamura, Takashi Toyama

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(23), P. 4629 - 4644.e9

Published: Nov. 14, 2024

Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, preventing unrestrained (phospho)lipid peroxidation by reducing phospholipid hydroperoxides (PLOOH). However, contribution other peroxidases in ferroptosis protection remains unclear. We show that cells lacking GPX4 still exhibit substantial PLOOH-reducing capacity, suggesting a alternative PLOOH peroxidases. By scrutinizing potential candidates, we found although overexpression peroxiredoxin 6 (PRDX6), thiol-specific antioxidant enzyme with reported activity, failed to prevent its genetic loss sensitizes cancer ferroptosis. Mechanistically, uncover PRDX6, beyond known acts as selenium-acceptor protein, facilitating intracellular selenium utilization and efficient incorporation into selenoproteins, including GPX4. Its physiological significance was demonstrated reduced expression Prdx6-deficient mouse brains increased sensitivity PRDX6-deficient tumor xenografts mice. Our study highlights PRDX6 critical player directing cellular dictating sensitivity.

Language: Английский

Citations

5
Recommendations for robust and reproducible research on ferroptosis DOI
Eikan Mishima, Toshitaka Nakamura, Sebastian Doll

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Language: Английский

Citations

0
Apoptotic cell death induced by copper (II), manganese (II) and silver (I) complexes containing bridging dicarboxylate and 1,10-phenanthroline ligands: one of the multi-modes of anticancer activity? DOI Creative Commons
E. J. O’Sullivan, Denis O’Shea, Michael Devereux

et al.

BioMetals, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Abstract Cu(II), Mn(II) and Ag(I) complexes incorporating bridging dicarboxylate 1,10-phenanthroline ligands have exhibited anti-cancer potential with significant in vitro vivo cytotoxic efficacies. Our study focuses on regulated cell death process of apoptosis as a mode action the activity by complexes. Cytotoxicity screening demonstrated all metal-dicarboxylate-phenanthroline exhibit superior compared to their non-phenanthroline containing precursors, addition cisplatin. The Cu(II) were shown induce reactive oxygen species (ROS) but this was not observed for analogues. Furthermore, found be induced metal-phenanthroline varying degrees contingent type metal centre complex. Apoptotic gene expression analysis established predominant activation intrinsic apoptotic pathway, co-stimulation extrinsic pathway some cases. mechanistic data provided within highlights multi-modal present, warranting continued investigation biological modes beyond induction.

Language: Английский

Citations

0
Improving understanding of ferroptosis: molecular mechanisms, connection with cellular senescence and implications for aging DOI Creative Commons

Diego De León-Oliva,

Diego Liviu Boaru,

Ana Minaya‐Bravo

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(21), P. e39684 - e39684

Published: Oct. 24, 2024

Language: Английский

Citations

3
Roquin-2 promotes oxidative stress-induced cell death by ubiquitination-dependent degradation of TAK1 DOI Creative Commons
Yusuke Hirata,

Yuya Nakata,

Hiromu Komatsu

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 221, P. 31 - 39

Published: May 8, 2024

Reactive oxygen species (ROS) are highly reactive and their accumulation causes oxidative damage to cells. Cells maintain survival upon mild stress with anti-oxidative systems, such as the kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related 2 (Nrf2) system. On other hand, severe stress, cells undergo regulated cell death, including apoptosis, for eliminating damaged To execute efficient need turn off anti-oxidant while triggering death. However, it remains unknown how orchestrate these two conflicting systems under excessive stress. Herein, we show that when exposed damage, an E3 ubiquitin ligase Roquin-2 (also known RC3H2) plays a key role in switching fate from death by terminating activation of transforming growth factor-β-activated kinase (TAK1), positive regulator Nrf2 activation. interacted TAK1 via four cysteine residues (C96, C302, C486, C500) susceptible participate oligomer formation disulfide bonds, promoting K48-linked polyubiquitination degradation TAK1. was inactivated lethal wild-type mouse embryonic fibroblast (MEF) cells, whereas sustained conferred resistance deficient which reversed pharmacological or genetic inhibition These data demonstrate response ROS exposure, promotes ubiquitination suppress activation, thereby contributes providing insight into pathogenesis stress-related diseases, cancer.

Language: Английский

Citations

2
Targeting ferroptosis for treating kidney disease DOI Creative Commons
Eikan Mishima

Clinical and Experimental Nephrology, Journal Year: 2024, Volume and Issue: 28(9), P. 866 - 873

Published: April 22, 2024

Abstract Ferroptosis is a type of regulated cell death hallmarked by iron-mediated excessive lipid oxidation. Over the past decade since coining term ferroptosis, advances in research have led to identification intracellular processes that regulate ferroptosis such as GSH-GPX4 pathway and FSP1-coenzyme Q 10 /vitamin K pathway. From disease perspective, involvement pathological conditions including kidney has attracted attention. In terms renal pathophysiology, been widely investigated for its ischemia–reperfusion injury, nephrotoxin-induced damage other diseases. Therefore, therapeutic interventions targeting are expected become new approach these However, when considering target, careful consideration must be given (i) which cells, (ii) mode, (iii) stage or temporal window disease. next decade, elucidation true setting human, development clinically applicable effective drugs target warranted.

Language: Английский

Citations

1
Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria DOI Creative Commons
Yusuke Hirata, Yuto Yamada,

Soma Taguchi

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(12)

Published: Dec. 6, 2024

Abstract Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such (10 E ,12 Z )-octadecadienoic acid and α-eleostearic (ESA), induced GPX4 degradation, generation mitochondrial reactive oxygen species (ROS) lipid peroxides, ultimately ferroptosis in cancer cell lines, including HT1080 A549 cells, which were suppressed by either pharmacological blockade CMA or genetic deletion LAMP2A, a crucial molecule CMA. Mitochondrial ROS sufficient necessary CMA-dependent degradation. Oral administration an ESA-rich oil attenuated xenograft tumor growth wild-type, but not that LAMP2A -deficient accompanied increased peroxidation, death. Our study establishes mitochondria key target to trigger peroxidation providing insight into ferroptosis-based therapy.

Language: Английский

Citations

1
Physiology in Perspective DOI

Nikki Forrester

Physiology, Journal Year: 2024, Volume and Issue: 39(2), P. 60 - 60

Published: Jan. 24, 2024

Language: Английский

Citations

0
PRDX6 dictates ferroptosis sensitivity by directing cellular selenium mobilization DOI Open Access
Junya Ito, Toshitaka Nakamura, Takashi Toyama

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 5, 2024

Summary Selenium-dependent glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis and prevents unrestrained (phospho)lipid peroxidation by directly reducing phospholipid hydroperoxides (PLOOH) to their corresponding alcohols. However, it remains unclear whether other peroxidases can also contribute prevention, albeit a varying degree. Here we show that cells lacking GPX4 still exhibit substantial PLOOH reduction capacity, arguing for presence alternative peroxidases. By scrutinizing potential candidates, showed while overexpression peroxiredoxin 6 (PRDX6), thiol-specific antioxidant enzyme with reported PLOOH-reducing activity, failed prevent ferroptosis, its genetic loss markedly sensitizes cancer ferroptosis. Mechanistically, uncover PRDX6 facilitates intracellular selenium handling, which crucial incorporation into selenoproteins, including GPX4. Consequently, modulates expression, thereby dictating sensitivity undergo Our study highlights as critical factor in prevention directing cellular mobilization.

Language: Английский

Citations

0