Ceramide synthase 6 induces mitochondrial dysfunction and apoptosis in hemin-treated neurons by impairing mitophagy...

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality.
• Mechanisms of neuronal injury following ICH are not fully understood.
• Sphingolipid metabolism plays a role in neuronal health and disease.

Purpose of the Study:

• To investigate alterations in neuronal sphingolipid metabolism after ICH.
• To explore the role of ceramide synthase 6 (CERS6) in neuronal injury post-ICH.
• To elucidate the relationship between ceramide metabolism and mitophagy in neurons.

Main Methods:

• Lipidomics analysis to profile sphingolipid alterations.
• Western blot and live-cell imaging to assess mitochondrial quality and mitophagy.
• CERS6 knockdown to evaluate its functional impact on neuronal injury.

Main Results:

• Hemin treatment significantly upregulated CERS6-dependent C16 ceramide biosynthesis.
• CERS6 knockdown ameliorated mitochondrial dysfunction and reduced neuronal apoptosis.
• CERS6 knockdown restored impaired neuronal mitophagy and reduced neuronal apoptosis.

Conclusions:

• CERS6 promotes neuronal apoptosis by impairing mitophagy through interaction with sequestosome 1.
• Dysregulated ceramide metabolism, specifically CERS6 activity, contributes to neuronal injury post-ICH.
• Targeting CERS6 represents a potential therapeutic strategy for managing intracerebral hemorrhage.