FUN14 domain-containing protein 2
phosphatidylinositol-3,4,5-trisphosphate binding
Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway.
Platelets undergo apoptosis in response to a variety of stimuli in the circulation. Mitochondria in platelets are essential for their apoptosis. Specifically, pro-survival protein BCL-x<sub>L</sub> on mitochondria is the key regulator of platelet lifespan. Here we identify an outer mitochondrial membrane protein FUNDC2 for platelet survival. FUNDC2 knockout mice carrying excessively apoptotic platelets exhibit thrombocytopenia in response to hypoxia. Mechanistically, FUNDC2 binds the lipid PIP3 via its unique, highly conserved N-terminal motif. FUNDC2 deficiency abrogates the phosphorylation of AKT and its substrate BAD in a PIP3/PI3K-dependent manner, which suppresses BCL-x<sub>L</sub>. Indeed, FUNDC2 deficiency shortens the platelet lifespan under stress. Thus, this FUNDC2/AKT/BCL-x<sub>L</sub> axis signifies a balance between platelet survival and apoptosis at the single organelle level and provides new insight for platelet-related diseases as well.