4.6 Article

Acid sphingomyelinase promotes mitochondrial dysfunction due to glutamate-induced regulated necrosis

Journal

JOURNAL OF LIPID RESEARCH
Volume 59, Issue 2, Pages 312-329

Publisher

ELSEVIER
DOI: 10.1194/jlr.M080374

Keywords

brain lipids; ferroptosis; glutamate/cystine antiporter; lipids/peroxidation; mitochondria; sphingolipids; sirtuin; oligodendrocytes

Funding

  1. National Institutes of Health [R01NS083544, R01DK073336, P30 GM103339]
  2. Veterans Affairs Merit Award [I01BX002991]
  3. US Public Health Service [S10OD018113]
  4. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK073336] Funding Source: NIH RePORTER
  5. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P30GM103339] Funding Source: NIH RePORTER
  6. NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS083544] Funding Source: NIH RePORTER
  7. Veterans Affairs [I01BX002991] Funding Source: NIH RePORTER

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Inhibiting the glutamate/cystine antiporter system x(c)(-), 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.

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