Induction of Cell Death by Dietary Fatty Acids

项目总结/摘要 调节性细胞死亡对于正常发育和整个成年期的组织维持至关重要。 最近描述的一种调节性细胞死亡形式，铁凋亡，与铁依赖性积累有关 氧化脂质的含量。亚铁凋亡在生物化学上不同于细胞凋亡，细胞凋亡是研究最充分的形式。 调节细胞死亡。铁凋亡是由细胞内代谢失衡引起的，而不是由诱导 促死亡凋亡蛋白。使用模式线虫秀丽隐杆线虫，我们发现了一种 在饮食摄入ω-6多不饱和脂肪酸后，生育力惊人地降低。我们发现 在整个发育过程中，ω-6脂肪会导致生殖细胞死亡，但不会导致体细胞死亡，而这种饮食- 诱导的细胞死亡在很大程度上独立于经典的凋亡途径。我们最近发现这种细菌 细胞死亡受小分子铁蛋白分解特异性抑制剂和诱导剂以及 操纵细胞中的铁水平，确定铁凋亡是膳食脂肪诱导的细胞死亡模式 in C.优雅在这个应用中，我们建议检查脂质过氧化物生产的细胞内位点， 性腺，并表征饮食诱导细胞死亡的新遗传调节剂，以阐明 该铁凋亡在组织、细胞和分子水平上受到调节。将测试铁凋亡的修饰剂 在哺乳动物癌细胞系中。此外，我们将剖析饮食组织特异性的机制， 诱导的铁凋亡以及线粒体脂质和代谢在调节铁凋亡中的作用。我们 拟议的研究将通过进一步的研究， 使用遗传学方法剖析饮食诱导的铁凋亡新现象所涉及的机制， 易处理的动物模型。我们的项目是创新和独特的，因为它检查饮食中的欧米茄-6脂肪酸- 在动物中诱导铁凋亡，它揭示了生殖细胞对这种类型的调节细胞的脆弱性 死亡

Project Summary/Abstract Regulated cell death is essential for proper development and for tissue maintenance throughout adulthood. A recently described form of regulated cell death, ferroptosis, is associated with iron-dependent accumulation of oxidized lipids in the cell. Ferroptosis is biochemically distinct from apoptosis, the most well-studied form of regulated cell death. Ferroptosis is induced by metabolic imbalances within the cell, rather than by induction of pro-death apoptotic proteins. Using the model nematode Caenorhabditis elegans, we discovered an astonishing reduction in fertility upon dietary ingestion of omega-6 polyunsaturated fatty acids. We found that the omega-6 fats caused death of germ cells, but not somatic cells, throughout development, and this dietary- induced cell death was largely independent of the classical apoptosis pathway. We recently found that germ cell death is modulated by small molecule ferroptosis-specific inhibitors and inducers, as well as by manipulating iron levels in cells, establishing that ferroptosis is the mode of cell death induced by dietary fats in C. elegans. In this application, we propose to examine the intracellular sites of lipid peroxide production in the gonad, and characterize new genetic modulators of dietary-induced cell death to elucidate the ways in which ferroptosis is regulated at the tissue, cellular and molecular levels. Modifiers of ferroptosis will be tested in mammalian cancer cell lines. Furthermore, we will dissect the mechanisms of tissue-specificity of dietary- induced ferroptosis and the roles of mitochondrial lipids and metabolism in modulating ferroptosis. Our proposed research will impact both the developmental biology field and the cell death field by further dissecting the mechanisms involved in the novel phenomenon of diet-induced ferroptosis using a genetically tractable animal model. Our project is innovative and unique, because it examines dietary omega-6 fatty acid- induction of ferroptosis in an animal, and it reveals the vulnerability of germ cells to this type of regulated cell death.