Department of Pharmacy, Institute of Pharmacy and Food, University of Havana, 222 St. # 2317, La Coronela, La Lisa, Havana 13600, Cuba.
Cell Death and Inflammation Unit, VIB Center for Inflammation Research (IRC), 9052 Ghent, Belgium.
Cells. 2023 Feb 24;12(5):735. doi: 10.3390/cells12050735.
Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.
铁死亡是一种由膜中多不饱和脂肪酸（PUFAs）的过度过氧化驱动的铁依赖性细胞死亡。越来越多的证据表明，诱导铁死亡是癌症治疗研究的一种前沿策略。尽管线粒体在细胞代谢、生物能量学和细胞死亡中起着至关重要的作用，但它们在铁死亡中的功能仍知之甚少。最近，线粒体被阐明为半胱氨酸剥夺诱导的（CDI）铁死亡中的一个重要组成部分，这为寻找新的铁死亡诱导化合物（FINs）提供了新的靶点。在这里，我们确定了天然线粒体解偶联剂 nemorosone 是癌细胞中的铁死亡诱导剂。有趣的是，nemorosone 通过双重机制触发铁死亡。除了通过阻断 System xc 胱氨酸/谷氨酸反向转运蛋白（SLC7A11）来降低谷胱甘肽（GSH）水平外，nemorosone 通过诱导血红素加氧酶-1（HMOX1）增加细胞内不稳定的 Fe 池。有趣的是，nemorosone 的一种结构变体（-甲基化 nemorosone），已经失去了解偶联线粒体呼吸的能力，不再引发细胞死亡，这表明通过线粒体解偶联破坏线粒体生物能量学对于 nemorosone 诱导的铁死亡是必要的。我们的结果为通过线粒体解偶联诱导的铁死亡杀死癌细胞开辟了新的机会。
