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Abstract
Inhibiting the glutamate/cystine antiporter system xc-, a key antioxidant defense machinery in the CNS, could trigger a novel form of regulated necrotic cell death, ferroptosis. The underlying mechanisms of system xc--dependent cell demise were elucidated using primary oligodendrocytes (OLs) treated with glutamate to block system xc- function. Pharmacological analysis revealed ferroptosis as a major contributing factor to glutamate-initiated OL death. A sphingolipid profile showed elevations of ceramide species and sphingosine that were preventable by inhibiting of an acid sphingomyelinase (ASM) activity. OL survival was enhanced by both downregulating ASM expression and blocking ASM activity. Glutamate-induced ASM activation seems to involve posttranscriptional mechanisms and was associated with a decreased GSH level. Further investigation of the mechanisms of OL response to glutamate revealed enhanced reactive oxygen species production, augmented lipid peroxidation, and opening of the mitochondrial permeability transition pore that were attenuated by hindering ASM. Of note, knocking down sirtuin 3, a deacetylase governing the mitochondrial antioxidant system, reduced OL survival. The data highlight the importance of the mitochondrial compartment in regulated necrotic cell death and accentuate the novel role of ASM in disturbing mitochondrial functions during OL response to glutamate toxicity, which is essential for pathobiology in stroke and traumatic brain injury.
Highlights
Inhibiting the glutamate/cystine antiporter system xc, a key antioxidant defense machinery in the CNS, could trigger a novel form of regulated necrotic cell death, ferroptosis
Our data suggest that glutamate-triggered decline of intracellular GSH results in the activation of acid sphingomyelinase (ASM) and upregulation of sphingosine, which, in turn, inhibits the mitochondrial respiratory chain, leading to generation of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (MPTP), and necrotic cell death
Our studies provide the experimental evidence supporting the important role of system xc -dependent regulated necrosis in OL response to glutamate
Summary
Inhibiting the glutamate/cystine antiporter system xc , a key antioxidant defense machinery in the CNS, could trigger a novel form of regulated necrotic cell death, ferroptosis. The data highlight the importance of the mitochondrial compartment in regulated necrotic cell death and accentuate the novel role of ASM in disturbing mitochondrial functions during OL response to glutamate toxicity, which is essential for pathobiology in stroke and traumatic brain injury.—Novgorodov, S. The uncovering of necroptosis and ferroptosis as the alternative forms of programmed cell death has resulted in a few studies implicating regulated necrotic cell death as an important contributing factor in tumor suppression, neurodegeneration, and ischemia/reperfusion (IR) tissue injury [2, 3].
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