Recently, we reported that the Cimicifuga racemosa extract Ze 450 mediated protection from oxidative cell damage through a metabolic shift from oxidative phosphorylation to glycolysis. Here, we investigated the molecular mechanisms underlying the effects of Ze 450 against ferroptosis in neuronal cells, with a particular focus on mitochondria. The effects of Ze 450 on respiratory complex activity and hallmarks of ferroptosis were studied in isolated mitochondria and in cultured neuronal cells, respectively. In addition, Caenorhabditis elegans served as a model organism to study mitochondrial damage and longevity in vivo. We found that Ze 450 directly inhibited complex I activity in mitochondria and enhanced the metabolic shift towards glycolysis via cMyc and HIF1α regulation. The protective effects against ferroptosis were mediated independently of estrogen receptor activation and were distinct from effects exerted by metformin. In vivo, Ze 450 protected C. elegans from the mitochondrial toxin paraquat and promoted longevity in a dose-dependent manner. In conclusion, Ze 450 mediated a metabolic shift to glycolysis via direct effects on mitochondria and altered cell signaling, thereby promoting sustained cellular resilience to oxidative stress in vitro and in vivo.

中文翻译：

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Cimicifuga racemosa Extract Ze 450 重新平衡能量代谢并促进长寿

最近，我们报道了总状升麻提取物 Ze 450 通过从氧化磷酸化到糖酵解的代谢转变介导了对氧化细胞损伤的保护。在这里，我们研究了 Ze 450 对神经元细胞铁死亡作用的潜在分子机制，特别关注线粒体。分别在分离的线粒体和培养的神经元细胞中研究了 Ze 450 对呼吸复合体活动和铁死亡标志的影响。此外，秀丽隐杆线虫作为模型生物研究体内线粒体损伤和寿命。我们发现 Ze 450 直接抑制线粒体中复合物 I 的活性，并通过 cMyc 和 HIF1α 调节增强向糖酵解的代谢转变。对铁死亡的保护作用独立于雌激素受体激活介导，并且与二甲双胍发挥的作用不同。在体内，Ze 450 保护秀丽隐杆线虫免受线粒体毒素百草枯的侵害，并以剂量​​依赖性方式延长寿命。总之，Ze 450 通过直接作用于线粒体和改变细胞信号来介导代谢转变为糖酵解，从而促进细胞在体外和体内对氧化应激的持续恢复能力。