- Title
- Differential cell death decisions in the testis: evidence for an exclusive window of ferroptosis in round spermatids
- Creator
- Bromfield, Elizabeth G.; Walters, Jessica L. H.; Nixon, Brett; Cafe, Shenae L.; Bernstein, Ilana R.; Stanger, Simone J.; Anderson, Amanda L; Aitken, R. John; McLaughlin, Eileen A.; Dun, Matthew D.; Gadella, Barend M.
- Relation
- NHMRC.APP1138701
- Relation
- Molecular Human Reproduction Vol. 25, Issue 5, p. 241-256
- Publisher Link
- http://dx.doi.org/10.1093/molehr/gaz015
- Publisher
- Oxford University Press
- Resource Type
- journal article
- Date
- 2019
- Description
- 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.
- Subject
- ferroptosis; oxidtive stress; germ cell; lipid peroxidation; lipoxygenase; infertility; cell death; spermatid
- Identifier
- http://hdl.handle.net/1959.13/1415929
- Identifier
- uon:36974
- Identifier
- ISSN:1360-9947
- Language
- eng
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