Crosstalk between ferroptosis and sarmoptosis

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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.