4 research outputs found
Determination of the Subcellular Localization and Mechanism of Action of Ferrostatins in Suppressing Ferroptosis
Ferroptosis
is a form of nonapoptotic cell death characterized
by the unchecked accumulation of lipid peroxides. Ferrostatin-1 and
its analogs (ferrostatins) specifically prevent ferroptosis in multiple
contexts, but many aspects of their molecular mechanism of action
remain poorly described. Here, we employed stimulated Raman scattering
(SRS) microscopy coupled with small vibrational tags to image the
distribution of ferrostatins in cells and found that they accumulate
in lysosomes, mitochondria, and the endoplasmic reticulum. We then
evaluated the functional relevance of lysosomes and mitochondria to
ferroptosis suppression by ferrostatins and found that neither is
required for effective ferroptosis suppression
P2X1, P2X4, and P2X7 Receptor Knock Out Mice Expose Differential Outcome of Sepsis Induced by α-Haemolysin Producing Escherichia coli.
α-haemolysin (HlyA)-producing Escherichia coli commonly inflict severe urinary tract infections, including pyelonephritis, which comprises substantial risk for sepsis. In vitro, the cytolytic effect of HlyA is mainly mediated by ATP release through the HlyA pore and subsequent P2X1/P2X7 receptor activation. This amplification of the lytic process is not unique to HlyA but is observed by many other pore-forming proteins including complement-induced haemolysis. Since free hemoglobin in the blood is known to be associated with a worse outcome in sepsis one could speculate that inhibition of P2X receptors would ameliorate the course of sepsis. Surprisingly, this study demonstrates that [Formula: see text] and [Formula: see text] mice are exceedingly sensitive to sepsis with uropathogenic E. coli. These mice have markedly lower survival, higher cytokine levels and activated intravascular coagulation. Quite the reverse is seen in [Formula: see text] mice, which had markedly lower cytokine levels and less coagulation activation compared to controls after exposure to uropathogenic E. coli. The high cytokine levels in the [Formula: see text] mouse are unexpected, since P2X7 is implicated in caspase-1-dependent IL-1β production. Here, we demonstrate that IL-1β production during sepsis with uropathogenic E. coli is mediated by caspase-8, since caspase-8 and RIPK3 double knock out mice show substantially lower cytokine during sepsis and increased survival after injection of TNFα. These data support that P2X7 and P2X4 receptor activation has a protective effect during severe E. coli infection
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Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Ferrostatin-1 (Fer-1) inhibits ferroptosis,
a form of regulated,
oxidative, nonapoptotic cell death. We found that Fer-1 inhibited
cell death in cellular models of Huntington’s disease (HD),
periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1
inhibited lipid peroxidation, but not mitochondrial reactive oxygen
species formation or lysosomal membrane permeability. We developed
a mechanistic model to explain the activity of Fer-1, which guided
the development of ferrostatins with improved properties. These studies
suggest numerous therapeutic uses for ferrostatins, and that lipid
peroxidation mediates diverse disease phenotypes
Recommended from our members
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Ferrostatin-1 (Fer-1) inhibits ferroptosis,
a form of regulated,
oxidative, nonapoptotic cell death. We found that Fer-1 inhibited
cell death in cellular models of Huntington’s disease (HD),
periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1
inhibited lipid peroxidation, but not mitochondrial reactive oxygen
species formation or lysosomal membrane permeability. We developed
a mechanistic model to explain the activity of Fer-1, which guided
the development of ferrostatins with improved properties. These studies
suggest numerous therapeutic uses for ferrostatins, and that lipid
peroxidation mediates diverse disease phenotypes