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Differential cell death decisions in the testis: Evidence for an exclusive window of ferroptosis in round spermatids

Journal Article


Abstract


  • Oxidative stress is a major aetiology in many pathologies, including that of male infertility. Recent evidence in somatic cells has linked oxidative stress to the induction of a novel cell death modality termed ferroptosis. However, the induction of this iron-regulated, caspase-independent cell death pathway has never been explored outside of the soma. Ferroptosis is initiated through the inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and is exacerbated by the activity of arachidonate 15-lipoxygenase (ALOX15), a lipoxygenase enzyme that facilitates lipid degradation. Here, we demonstrate that male germ cells of the mouse exhibit hallmarks of ferroptosis including; a caspase-independent decline in viability following exposure to oxidative stress conditions induced by the electrophile 4-hydroxynonenal or the ferroptosis activators (erastin and RSL3), as well as a reciprocal upregulation of ALOX15 and down regulation of GPX4 protein expression. Moreover, the round spermatid developmental stage may be sensitized to ferroptosis via the action of acyl-CoA synthetase long-chain family member 4 (ACSL4), which modifies membrane lipid composition in a manner favourable to lipid peroxidation. This work provides a clear impetus to explore the contribution of ferroptosis to the demise of germline cells during periods of acute stress in in vivo models.

Publication Date


  • 2019

Citation


  • Bromfield, E. G., Walters, J. L. H., Cafe, S. L., Bernstein, I. R., Stanger, S. J., Anderson, A. L., . . . Nixon, B. (2019). Differential cell death decisions in the testis: Evidence for an exclusive window of ferroptosis in round spermatids. Molecular Human Reproduction, 25(5), 241-256. doi:10.1093/molehr/gaz015

Scopus Eid


  • 2-s2.0-85065084581

Start Page


  • 241

End Page


  • 256

Volume


  • 25

Issue


  • 5

Abstract


  • Oxidative stress is a major aetiology in many pathologies, including that of male infertility. Recent evidence in somatic cells has linked oxidative stress to the induction of a novel cell death modality termed ferroptosis. However, the induction of this iron-regulated, caspase-independent cell death pathway has never been explored outside of the soma. Ferroptosis is initiated through the inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and is exacerbated by the activity of arachidonate 15-lipoxygenase (ALOX15), a lipoxygenase enzyme that facilitates lipid degradation. Here, we demonstrate that male germ cells of the mouse exhibit hallmarks of ferroptosis including; a caspase-independent decline in viability following exposure to oxidative stress conditions induced by the electrophile 4-hydroxynonenal or the ferroptosis activators (erastin and RSL3), as well as a reciprocal upregulation of ALOX15 and down regulation of GPX4 protein expression. Moreover, the round spermatid developmental stage may be sensitized to ferroptosis via the action of acyl-CoA synthetase long-chain family member 4 (ACSL4), which modifies membrane lipid composition in a manner favourable to lipid peroxidation. This work provides a clear impetus to explore the contribution of ferroptosis to the demise of germline cells during periods of acute stress in in vivo models.

Publication Date


  • 2019

Citation


  • Bromfield, E. G., Walters, J. L. H., Cafe, S. L., Bernstein, I. R., Stanger, S. J., Anderson, A. L., . . . Nixon, B. (2019). Differential cell death decisions in the testis: Evidence for an exclusive window of ferroptosis in round spermatids. Molecular Human Reproduction, 25(5), 241-256. doi:10.1093/molehr/gaz015

Scopus Eid


  • 2-s2.0-85065084581

Start Page


  • 241

End Page


  • 256

Volume


  • 25

Issue


  • 5