Novgorodov, Sergei A., Voltin, Joshua R., Gooz, Monika A., Li, Li, Lemasters, John, J. and Tatyana I., Gudz (2018) A novel role of acid sphingomyelinase in mitochondrial dysfunction due to glutamate-induced programmed necrosis. Journal of Lipid Research, 59 (2). pp. 312-329. ISSN 0022-22751539-7262

Abstract

The glutamate/cystine antiporter system xc - plays an important role in regulating extracellular glutamate levels and in maintaining intracellular cysteine/glutathione (GSH)-dependent antioxidant defense mechanisms in the brain. Blocking the system xc - -dependent pathway could trigger a novel form of programmed necrosis, ferroptosis, which has demonstrated an exciting potential for cancer therapy. Yet, the mechanisms of regulated necrosis in the neural cells and its relevance to neurological disease remain unexplored. Primary oligodendrocytes (OLs), unique myelin-forming cells in the CNS, were treated with glutamate to provoke system xc --mediated cell death. Pharmacological analysis revealed ferroptosis as a major contributing factor to glutamate-initiated OL death. Although RIP1 kinase inhibitor necrostatin-1 protected OLs from glutamate toxicity, there was no activation of the RIP1 and/or RIP3 kinase-mediated necroptosis signaling pathway, suggesting an offtarget effect of necrostatin-1. A quantitative lipidomics analysis showed a significant elevation of bioactive sphingolipids (ceramide and sphingosine) that was prevented by Reclast, a potent inhibitor of acid sphingomyelinase (ASM) activity. OL survival was enhanced by both down-regulating ASM expression and by blocking ASM activity, which suggests ASM plays a crucial role of in OL response to glutamate. Glutamate-induced ASM activation seems to involve post-transcriptional mechanisms and was associated with a decreased GSH level. Further investigation of the mechanisms of OL response to glutamate revealed enhanced ROS production, augmented lipid peroxidation and opening of the mitochondrial permeability transition pore (MPTP) that were attenuated by hindering ASM. Of note, knocking down SIRT3, a deacetylase governing the mitochondrial antioxidant system, attenuated OL survival, highlighting the protective impact of SIRT3 on glutamate-induced necrotic cell death. The data shed more light on the mechanisms of programmed necrotic cell death and accentuate the novel role of ASM in disturbing mitochondrial functions during OL response to glutamate toxicity, which could be important for pathobiology in stroke and traumatic brain injury.

Item Type:	Article
Date Deposited:	06 Mar 2018 00:45
Last Modified:	06 Mar 2018 00:45
URI:	https://oak.novartis.com/id/eprint/33648