BACH1通过ferroptotic FGF21分泌物抑制衰老,肥胖和寿命缩短
Hironari Nishizawa1, Mitsuyo Matsumoto2, Mie Yamanaka3
1Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Cell reports
|June 29, 2024
概括
由BACH1诱导的铁死会触发FGF21的释放,这是一种长寿因子. 这种分泌的FGF21促进细胞增殖,减少衰老,并对抗肥胖和寿命短等衰老表型.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生化学
- 衰老研究研究 衰老研究
背景情况:
- 铁亡是一种受调节的细胞死亡,由铁依赖的脂质过氧化驱动.
- 转录因子BACH1是已知的ferroptosis的诱导因子.
- 细胞衰老是一种与衰老相关的不可逆转的生长停止状态.
研究的目的:
- 调查BACH1诱导的铁死在细胞通信和衰老中的作用.
- 为了确定涉及铁质中介抗衰老作用的分泌因素.
- 阐明BACH1影响FGF21分泌的机制及其下游影响.
主要方法:
- 通过不朽化的小鼠胚胎纤维细胞 (iMEFs) 建立了一个细胞系统,通过BACH1再表达诱导铁亡.
- 分析了来自ferroptotic iMEFs的培养上游生物对它们对肝瘤细胞和纤维细胞的影响.
- 利用Fgf21淘汰模型来评估FGF21对观察到的表型的必要性.
- 研究了BACH1对Fgf21的转录调节及其对蛋白质降解途径的影响.
主要成果:
- 来自ferroptotic iMEFs的培养上游剂促进了受体细胞的增殖并抑制了受体细胞的衰老.
- BACH1诱导的铁亡显著增加了长寿因子FGF21的分泌.
- 抗衰老效应依赖于FGF21,因为Fgf21淘汰赛取消了这些效应.
- 通过抑制Sqstm1和Lamp2,BACH1通过转录激活Fgf21,从而增加ferroptotic应激,并通过抑制Sqstm1和Lamp2抑制FGF21的自降解.
- BACH1诱导的FGF21分泌改善了高脂肪饮食养小鼠的肥胖症,并延长了孕病小鼠的寿命.
结论:
- BACH1诱导的铁亡是FGF21的来源,FGF21是一种具有抗衰老特性的分泌因子.
- 铁酶介导的FGF21分泌为与年龄相关的疾病提供了一种新的治疗策略.
- 这些发现突显出铁和衰老过程之间存在显著的生理联系.
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