Abstract
Mitochondrial transplantation emerges as a novel therapeutic solution for ischemia/reperfusion injury (IRI) in various tissues. Platelets have recently been used in mitochondrial transplantation as readily-available donors of small-size platelet mitochondria (plt-mito). Interestingly, FUN14 Domain Containing 2 (FUNDC2), a protein highly-expressed in the outer membrane (OMM) of plt-mito, has been identified to maintain platelet survival under hypoxic condition. The current study determined whether and how FUNDC2 contributed to the therapeutic effect of plt-mito transplantation for hypoxia/reoxygenation (HR) injury. The results showed that incorporation of human plt-mito into SH-SY5Y cells rescued HR-induced mitochondrial malfunction and mitochondrial apoptotic pathway. Mechanistically, plt-mito transplantation led to an increased expression of FUNDC2 in the recipient cells. This protein induced mitochondrial translocation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) via its N-term, resulting in the stimulation of the protein kinase B (Akt)/forkhead box O3a (FOXO3a) pathway, which inhibited HR-induced mitochondrial accumulation of a mitochondrial target of FOXO3a, Bim, also known as a pro-apoptotic protein. Therefore, the FUNDC2/PIP3/Akt/FOXO3a axis may facilitate the incorporated plt-mito to restore mitochondrial function and cell viability of the recipient cells, and platelets may serve as readily-available sources of donor mitochondria that afford therapeutic benefits against IRI.