Molecular mechanisms of mitochondrial dysfunction in regulated necrotic cell death: Implications for stroke and traumatic brain injury
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Adams, Chad
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Abstract
Regulated cell death occurs through several mechanisms. The glutamate/cysteine antiporter (system xc) is an essential component of ferroptosis, a form of regulated necrosis. This antiporter is responsible for maintaining homeostatic levels of extracellular glutamate. If the function of this system is interrupted or damaged, it results in increased generation of reactive oxygen species and lipid peroxidation. Because traumatic brain injuries and strokes cause release of glutamate through damaged cell membranes and the blood brain barrier, this antiporter is essential. The mechanisms involved in ferroptosis have been studied in cancer cells, however the nuances of the mechanism are still largely unclear in neural cells. In addition to elevated extracellular glutamate, sphingolipids may play a regulatory role in this process. Sphingosine is a key sphingolipid that may trigger ferroptosis. Acid sphingomyelinase (ASM) makes sphingosine by cleaving sphingomyelin. This enzyme is believed to be activated by the increased glutamate, making it of interest in this project. ASM and its relationship to extracellular glutamate and the production of sphingosine makes it likely that it has a regulatory in ferroptosis. The results of the study draw attention to the importance of the cystine/glutamate (system xc-) antiporter. When the extracellular concentration of glutamate is elevated, this antiporter cannot supply cystine to produce glutathione, a protective antioxidant. Additionally, acid sphingomyelinase is activated in response to glutathione depletion and results in an increase in sphingosine and ceramide concentrations. The increase in these two bioactive sphingolipids disrupts the mitochondrial respiratory chain and results in oxidative damage and death of oligodendrocytes. The results of this study provide insight into how to protect oligodendrocytes and other brain cells from secondary injuries following traumatic brain injuries.
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ferroptosis, TBI, Traumatic brain injury