JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Stroke-induced brain injury involves mitochondrial dysfunction and cell death.
• Mechanisms of mitochondrial injury during cerebral ischemia/reperfusion (IR) are not well understood.
• Ceramide acts as a second messenger in apoptosis signaling.

Purpose of the Study:

• To investigate the mechanisms of mitochondrial injury in cerebral IR.
• To determine the role of ceramide in IR-induced mitochondrial dysfunction.
• To identify signaling pathways regulating ceramide biosynthesis during cerebral IR.

Main Methods:

• Assessed ceramide generation pathways (biosynthesis vs. hydrolysis) in cerebral IR.
• Investigated ceramide localization within mitochondria and its effect on mitochondrial function.
• Utilized JNK3-deficient mice to examine the role of JNK3 signaling in IR-induced ceramide production and mitochondrial damage.

Main Results:

• Cerebral IR elevated ceramide levels through de novo biosynthesis, not sphingomyelin hydrolysis.
• Ceramide accumulated in mitochondria due to post-translational activation of mitochondrial ceramide synthase.
• Exogenous ceramide mimicked IR-induced mitochondrial respiratory chain damage, while dihydroceramide did not.
• JNK3 deficiency abolished IR-induced ceramide generation and mitochondrial damage, reducing infarct volume.

Conclusions:

• Mitochondrial respiratory chain dysfunction in cerebral IR is caused by ceramide accumulation via stimulated mitochondrial ceramide synthase activity.
• JNK3 signaling plays a critical role in regulating ceramide biosynthesis during cerebral IR.
• Targeting JNK3-mediated ceramide production may offer a therapeutic strategy for stroke.