Acid Sphingomyelinase Promotes Mitochondrial Dysfunction Due to Glutamate-induced Regulated Necrosis

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2017 Dec 29

PMID 29282302

Citations 37

Authors

Sergei A Novgorodov

Joshua R Voltin

Monika A Gooz

Li Li

John J Lemasters

Tatyana I Gudz

Affiliations

Soon will be listed here.

Abstract

Inhibiting the glutamate/cystine antiporter system x, a key antioxidant defense machinery in the CNS, could trigger a novel form of regulated necrotic cell death, ferroptosis. The underlying mechanisms of system x-dependent cell demise were elucidated using primary oligodendrocytes (OLs) treated with glutamate to block system x 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.

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