Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure

Abstract

Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-017-2547-4) contains supplementary material, which is available to authorized users.

Metabolic networks in ferroptosis (Review)

“…In acute kidney failure, hemorrhagic stroke and nephrotoxic folic acid induce acute kidney injury, and inhibitors of ferroptosis (for example, ferrostatin-1) reduce the damage caused by cell sabotage. Ferrostatin-1 preserves renal function and decreases injury, oxidative stress and tubular cell death in mice with nephrotoxic folic acid-induced acute kidney injuries (17,58,59). Therefore, ferrostatin-1 may have a prophylactic effect in these non-neoplastic diseases.…”

“…Ferroptosis is a type of cellular sabotage that results in cell death, whereas apoptosis, pyroptosis and necroptosis are considered types of programmed cell death (16). Ferroptosis is not blocked by carbobenzoxy-valyl-alanyl-aspartyl-(O-me thyl)-fluoromethylketone, an inhibitor of caspase-dependent apoptosis and pyroptosis, or by necrostatin-1, an inhibitor of RIPK1-dependent necroptosis (17,18).…”

Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

“…Ferroptosis is a newly discovered form of regulated cell death that plays a major role in various diseases, including tumor, stoke, cold stress, acute kidney failure, and neural degeneration. 13,18,[29][30][31][32] As in TBI, a recent study reported that ferroptotic death possibly occurs at early time points after TBI in the pediatric rat CCI model due to elevated levels of 15-HpETE-PE in the brain cortex and hippocampus, along with increased expression of 15LO2 and decreased levels of GPX4. 19 However, the precise role of ferroptosis in adult rodents remains unknown.…”

Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

“…The role of ferroptosis as a cell death mechanism contributing to organ damage in sepsis has been hardly explored. Nevertheless, ferroptosis has been implicated in acute kidney failure and could be an important alternative cell death pathway during sepsis (Linkermann et al , ; Müller et al , ; Wenzel et al , ). The precise contribution and impact of each of above‐mentioned altered cellular processes have not been properly delineated and seem to depend on lipid composition and cell type (Ghosh & Rodrigues, ).…”