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

Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. 2017 May 27;: Authors: Müller T, Dewitz C, Schmitz J, Schröder AS, Bräsen JH, Stockwell BR, Murphy JM, Kunzendorf U, Krautwald S 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 contri...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Tags: Cell Mol Life Sci Source Type: research