2. Academic Validation
  3. Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway

Mitochondrial PIP3-binding protein FUNDC2 supports platelet survival via AKT signaling pathway

  • Cell Death Differ. 2019 Jan;26(2):321-331. doi: 10.1038/s41418-018-0121-8.
Qi Ma 1 2,  Chongzhuo Zhu 3,  Weilin Zhang 3,  Na Ta 3,  Rong Zhang 3,  Lei Liu 3,  Du Feng 4,  Heping Cheng 5,  Junling Liu 6,  Quan Chen 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 2 Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China. [email protected].
  • 3 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 4 Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
  • 5 Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
  • 6 Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
PMID: 29786068 DOI: 10.1038/s41418-018-0121-8
Abstract

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-xL 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-xL. Indeed, FUNDC2 deficiency shortens the platelet lifespan under stress. Thus, this FUNDC2/Akt/BCL-xL axis signifies a balance between platelet survival and Apoptosis at the single organelle level and provides new insight for platelet-related diseases as well.

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