Abstract
The lipid peroxide scavenger enzyme glutathione peroxidase 4 (GPX4) and its cofactor glutathione play a crucial role in the recently described programmed cell death, ferroptosis. Since mitochondria are the major sources of reactive oxygen species in mammalian cells the linkage between mitochondria, mitochondrial ROS generation and ferroptosis emerged quite early. As a result of alternative splicing human GPX4 has three different isoforms: long form (lGPX4), short form (sGPX4) and nuclear form (nGPX4) of which sGPX4 was found essential. To clarify the potential role of mitochondria in ferroptosis the localization of both the long and short versions of GPX4 and the only verified glutathione transport protein SLC25A11 was investigated by different in silico tools. Targeting of lGPX4 and sGPX4 to multiple organelles is possible as a number of rule- and neural network-based algorithms showed concordant results to specific pathways. Hence the mitochondrial localization of both isoforms on the base of in silico prediction is possible. Since sGPX4 was found in multiple organelles and non-canonical import pathways are presumable we also evaluated the previously used in silico methods in predicting the localization of a chimeric signal containing peptide CYP2B1 as well as a solely mitochondrial targeted CYP27A1. Our in silico results showed that only the CELLO prediction tool ranked mitochondrial import with meaningful possibility based on neighboring sequence composition. Summarily the possible mitochondrial localization of both long and short isoforms of GPX4 and the glutathione transporter SLC25A11 support the assumption that mitochondria play an important role in the pathways leading to ferroptosis.
Highlights
The water-soluble tripeptide glutathione (GSH) is exclusively synthesized in the cytosol where it can be found in millimolar range [1,2,3]
It is interesting to note that the neural network based algorithms rank endoplasmic reticulum import pathway highly: TargetP calculated some degree of mitochondrial localization, but processing of the long isoform of GPX4 (lGPX4) peptide through the secretory pathway (SP) was considered to be more than 3 times as probable while ER localization calculated by Predotar was almost as probable as mitochondrial (Table 1)
The only key protein that was recognized up to date to have a role in ferroptosis is the lipid peroxide scavenger glutathione peroxidase 4 (GPX4)
Summary
The water-soluble tripeptide glutathione (GSH) is exclusively synthesized in the cytosol where it can be found in millimolar range [1,2,3]. As a cofactor of glutathione peroxidase it quenches hydrogen-peroxide and repairs lipid oxidation, scavenges reactive nitrogen species (RNS), the ratio of its reduced/oxidized form (GSH/GSSG) serves as a sensitive factor of cellular redox state, it mediates redox signaling, it conjugates with drugs and xenobiotics under the catalysis of glutathione S-transferases (GSTs) [4]. Looking at this list of important functions it is not surprising that extensive GSH depletion was involved in different cell deaths such as apoptosis, necroptosis and autophagy [5,6,7,8].
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