Differential cell death decisions in the testis: evidence for an exclusive window of ferroptosis in round spermatids.
Mol Hum Reprod
; 25(5): 241-256, 2019 05 01.
Article
em En
| MEDLINE
| ID: mdl-30865280
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Espermátides
/
Peroxidação de Lipídeos
/
Oxidantes
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Regulação da Expressão Gênica no Desenvolvimento
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Ferroptose
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Mol Hum Reprod
Assunto da revista:
BIOLOGIA MOLECULAR
/
MEDICINA REPRODUTIVA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Austrália