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

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• The glutamate/cystine antiporter system x_c^- is crucial for CNS antioxidant defense.
• Inhibition of system x_c^- can induce ferroptosis, a regulated necrotic cell death pathway.
• Oligodendrocytes (OLs) are vital for CNS function and susceptible to oxidative stress.

Purpose of the Study:

• To elucidate the mechanisms of system x_c^--dependent cell death in primary oligodendrocytes.
• To investigate the role of acid sphingomyelinase (ASM) in glutamate-induced OL demise.
• To explore the involvement of mitochondrial dysfunction in this process.

Main Methods:

• Primary oligodendrocyte cultures treated with glutamate to inhibit system x_c^-.
• Pharmacological inhibition and genetic downregulation of acid sphingomyelinase (ASM).
• Sphingolipid profiling, reactive oxygen species (ROS) measurement, lipid peroxidation assays, and mitochondrial permeability transition pore analysis.

Main Results:

• Glutamate-induced OL death was significantly mediated by ferroptosis.
• Elevated ceramide and sphingosine levels were observed, preventable by ASM inhibition.
• ASM activation was linked to decreased GSH levels, increased ROS, lipid peroxidation, and mitochondrial dysfunction.
• Downregulating ASM or sirtuin 3 impaired OL survival.

Conclusions:

• Acid sphingomyelinase (ASM) plays a novel and critical role in mediating ferroptosis and mitochondrial dysfunction in oligodendrocytes.
• Targeting ASM may offer a therapeutic strategy for conditions involving glutamate toxicity, such as stroke and traumatic brain injury.
• Mitochondrial integrity is essential for regulating cell death pathways in response to oxidative stress.