Poindessous Virginie, Lazareth Helene, Crambert Gilles, Cheval Lydie, Sampaio Julio L, Pallet Nicolas
Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, Paris, France.
Université Paris-Cité, Paris, France.
iScience. 2024 Apr 16;27(6):109737. doi: 10.1016/j.isci.2024.109737. eCollection 2024 Jun 21.
Long-chain acyl-CoA synthetase family 4 (ACSL4) metabolizes long-chain polyunsaturated fatty acids (PUFAs), enriching cell membranes with phospholipids susceptible to peroxidation and drive ferroptosis. The role of ACSL4 and ferroptosis upon endoplasmic-reticulum (ER)-stress-induced acute kidney injury (AKI) is unknown. We used lipidomic, molecular, and cellular biology approaches along with a mouse model of AKI induced by ER stress to investigate the role of ACSL4 regulation in membrane lipidome remodeling in the injured tubular epithelium. Tubular epithelial cells (TECs) activate ACSL4 in response to STAT3 signaling. In this context, TEC membrane lipidome is remodeled toward PUFA-enriched triglycerides instead of PUFA-bearing phospholipids. TECs expressing ACSL4 in this setting are not vulnerable to ferroptosis. Thus, ACSL4 activity in TECs is driven by STAT3 signaling, but ACSL4 alone is not enough to sensitize ferroptosis, highlighting the significance of the biological context associated with the study model.
长链脂酰辅酶A合成酶家族4（ACSL4）代谢长链多不饱和脂肪酸（PUFA），使细胞膜富含易发生过氧化的磷脂并驱动铁死亡。ACSL4及铁死亡在内质网（ER）应激诱导的急性肾损伤（AKI）中的作用尚不清楚。我们运用脂质组学、分子生物学和细胞生物学方法，并结合ER应激诱导的AKI小鼠模型，来研究ACSL4调控在受损肾小管上皮细胞膜脂质组重塑中的作用。肾小管上皮细胞（TEC）响应信号转导和转录激活因子3（STAT3）信号而激活ACSL4。在此背景下，TEC膜脂质组向富含PUFA的甘油三酯而非含PUFA的磷脂重塑。在此环境中表达ACSL4的TEC对铁死亡不敏感。因此，TEC中的ACSL4活性由STAT3信号驱动，但仅ACSL4不足以使细胞对铁死亡敏感，这突出了与研究模型相关的生物学背景的重要性。
