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.
journal_name
Mol Hum Reprodjournal_title
Molecular human reproductionauthors
Bromfield EG,Walters JLH,Cafe SL,Bernstein IR,Stanger SJ,Anderson AL,Aitken RJ,McLaughlin EA,Dun MD,Gadella BM,Nixon Bdoi
10.1093/molehr/gaz015subject
Has Abstractpub_date
2019-05-01 00:00:00pages
241-256issue
5eissn
1360-9947issn
1460-2407pii
5379203journal_volume
25pub_type
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