A novel role of sphingolipids and mitochondria in glutamate-induced programmed necrosis in oligodendrocytes
FASEB JOURNAL(2018)
Abstract
Oligodendrocytes play a prominent role in axon myelination and provide trophic factors and substrates for neurons. Under pathological conditions (e.g., ischemia/reperfusion, traumatic brain injury and stroke), the increase in extracellular glutamate levels evokes oligodendrocyte cell death, thus contributing to neuronal dysfunction. In contrast to the activation of ionotropic glutamate receptors in neurons, glutamate induces cell death in oligodendrocytes by depleting cells of cystine through the reversal of glutamate/cystine antiport mediated by system x c − . Our experiment revealed ferroptosis as a major contributing factor to glutamate‐initiated primary oligodendrocytes (OLs) death, while the contribution of necroptosis and apoptosis was excluded both on biochemical and pharmacological ground. However, in contrast to general view that disintegration of plasma membrane as a result of uncontrolled lipid peroxidation is the final step in execution of ferroptotic program, we demonstrate that inhibitors of the mitochondrial permeability transition pore, (MPTP) cyclosporine A and NIM811, attenuate glutamate‐induced cell death without affecting lipid peroxidation. This suggests bioenergetic failure as the ultimate cause of cell demise. We also identified a novel controlling factor of ferroptosis‐like cell death in OLs, sphingosine, a sphingolipid whose level in the mitochondrial compartment is increased in response to glutamate. This leads to suppression of the respiratory chain and enhanced production of reactive oxygen species, which contributes to MPTP opening. Experiments indicate that the enhanced sphingosine level originates from activation of acid sphingomyelinase (ASM) in the lysosomal compartment, which produces ceramide with its subsequent hydrolysis to sphingosine by acid ceramidase. The results of these studies highlight a novel mechanism of ASM involvement in governing mitochondrial ROS production and integrity, and suggest an important role of ASM in system x c − ‐ dependent ferroptosis in the brain. Support or Funding Information Supported by NIH grants NS083544 (TIG) and RO1 DK073336 (JJL). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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Key words
sphingolipids,mitochondria,necrosis
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