Crosstalk between ferroptosis and sarmoptosis

铁缺乏症导致一种特定形式的铁依赖性程序性细胞死亡，其特征是谷胱甘肽耗尽、谷胱甘肽过氧化物酶4抑制和脂质过氧化，最终通过致命的Ca 2+稳态失调而执行。在铁凋亡的初始阶段，细胞上调NAD+消耗途径，如Sirtuin 3，一种使用NAD+作为底物的线粒体脱乙酰酶，以直接抵消活性氧的产生并产生NADPH，用于为谷胱甘肽还原酶提供燃料以恢复谷胱甘肽并保持谷胱甘肽过氧化物酶4活性。这个过程消耗NAD+。有趣的是，另一种与铁凋亡不同的程序性细胞死亡途径是由NAD+耗竭触发的。这种途径在从其细胞体切断的退化轴突中是活跃的，并且由于其涉及蛋白质SARM 1的二聚化而被创造为肉瘤样凋亡。肉瘤细胞凋亡的主要特征是NAD+消耗和其前体烟酰胺单核苷酸（NMN）的积累，但与铁细胞凋亡相似，也是JNK激酶激活和Ca 2+稳态失调。基于这些细胞死亡程序的明显重叠特征，我们认为存在铁凋亡和肌凋亡之间的串扰。我们推测，在铁凋亡过程中，NAD+消耗增加和JNK激酶抑制NMN生成酶的结合导致NMN/NAD+失衡，从而引发肌凋亡并激活死亡前致命的Ca 2+失调。另一方面，我们提出，sarmoptosis触发Sirtuin 3活性的功能障碍，由于缺乏其底物NAD+，这可能会导致GSSG/GSH失衡，在sarmoptosis和随后的特征，ferroptosis的执行。为了更深入地了解这些途径，因此，我们提出了研究，以研究标志性的肌细胞凋亡的铁细胞凋亡和抵抗铁细胞凋亡，以澄清是否抑制肌细胞凋亡保护对铁细胞凋亡，并阐明铁细胞凋亡的执行轴突变性的相关性。这项工作是高度相关的，因为它旨在阐明细胞生物学的基本方面。

Ferroptosis causes a specific form of iron-dependent programmed cell death characterized by glutathione depletion, inhibition of glutathione peroxidase 4 and lipid peroxidation that is finally executed by a fatal dysregulation of Ca2+ homeostasis. In the initial phase of ferroptosis, the cells upregulate NAD+-consuming pathways like Sirtuin 3, a mitochondrial deacetylase that uses NAD+ as substrate, to directly counteract production of reactive oxygen species and generate NADPH used to fuel glutathione reductase to recover glutathione and keeping glutathione peroxidase 4 active. This process consumes NAD+. Interestingly, another pathway of programmed cell death distinct form ferroptosis is triggered by NAD+ depletion. This pathway is active in degenerating axons severed from their cell bodies and is coined sarmoptosis because it involves dimerization of the protein SARM1. Sarmoptosis is characterized primarily by NAD+ depletion and accumulation of its precursor nicotinamide mononucleotide (NMN), but similar to ferroptosis also by activation of JNK kinases and a dysregulated Ca2+ homeostasis. Based on the obvious overlapping features of these cell death programs, we claim that a crosstalk between ferroptosis and sarmoptosis exists. We hypothesize that the combination of increased NAD+ consumption and inhibition of NMN-generating enzymes by JNK kinases during ferroptosis results in a disbalance of NMN/NAD+ that triggers sarmoptosis and activates the fatal Ca2+ dysregulation that precedes demise. On the other hand, we propose that sarmoptosis triggers a dysfunction of Sirtuin 3 activity caused by lack of its substrate NAD+ which probably results in a GSSG/GSH disbalance during the execution of sarmoptosis and subsequent features of ferroptosis. To obtain more insight into these pathways, we therefore propose studies to study hallmarks of sarmoptosis in ferroptosis and resistance against ferroptosis, to clarify whether inhibiting sarmoptosis protects against ferroptosis and to elucidate the relevance of ferroptosis for the execution of axonal degeneration. This work is of high relevance as it aims to elucidate fundamental aspects of cell biology.