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

Elizabeth G. Bromfield, Jessica L.H. Walters, Shenae L. Cafe, Ilana R. Bernstein, Simone J. Stanger, Amanda L. Anderson, R. John Aitken, Eileen A. McLaughlin, Matthew D. Dun, Barend M. Gadella, Brett Nixon

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3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)241-256
Number of pages16
JournalMolecular Human Reproduction
Volume25
Issue number5
DOIs
Publication statusPublished - 2019
Externally publishedYes

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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. https://doi.org/10.1093/molehr/gaz015