FUNDC2 regulates platelet activation through AKT/GSK-3β/cGMP axis

Area of Science:

• Cellular biology
• Biochemistry
• Hematology

Background:

• Mitochondrial protein FUNDC2 is involved in AKT phosphorylation and platelet apoptosis.
• AKT kinase plays a key role in signal transduction for platelet aggregation.

Purpose of the Study:

• To investigate the role of FUNDC2 in platelet activation and aggregation.
• To elucidate the molecular mechanisms underlying FUNDC2's function in platelets.

Main Methods:

• Assessed platelet aggregation using various agonists (ADP, collagen, ristocetin/VWF, thrombin).
• Utilized in vivo assays for tail bleeding and thrombus formation in FUNDC2-knockout mice.
• Investigated the phosphorylation status of AKT and GSK-3β.
• Analyzed the role of cyclic guanosine monophosphate (cGMP) and clot retraction.

Main Results:

• FUNDC2 deficiency significantly reduced platelet aggregation in response to multiple agonists.
• FUNDC2-knockout mice exhibited impaired hemostasis and thrombosis.
• FUNDC2 deficiency led to decreased AKT and GSK-3β phosphorylation in a PI3K-dependent manner.
• The FUNDC2/AKT/GSK-3β/cGMP pathway was identified as critical for platelet activation and clot retraction.

Conclusions:

• FUNDC2 positively regulates platelet functions through the AKT/GSK-3β/cGMP signaling pathway.
• This pathway is essential for normal platelet activation, aggregation, hemostasis, and thrombosis.
• Findings provide novel insights into platelet-related diseases and potential therapeutic targets.