Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis
| Autor: | Monika A. Gooz, Joshua Voltin, John J. Lemasters, Li Li, Tatyana I. Gudz, Sergei A. Novgorodov |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ceramide glutamate/cystine antiporter Glutamic Acid QD415-436 Mitochondrion Biochemistry Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Mice Necrosis Endocrinology Pregnancy medicine Animals brain lipids Cells Cultured Research Articles sphingolipids Sphingosine Glutamate receptor Cell Biology Glutathione Sphingolipid ferroptosis Cell biology Mitochondria Rats Oligodendroglia 030104 developmental biology Sphingomyelin Phosphodiesterase chemistry Mitochondrial permeability transition pore lipids/peroxidation Female Acid sphingomyelinase medicine.drug |
| Zdroj: | Journal of Lipid Research, Vol 59, Iss 2, Pp 312-329 (2018) |
| ISSN: | 1539-7262 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|