Downregulation of STIM2 improves neuronal survival after traumatic brain injury by alleviating calcium overload and mitochondrial dysfunction

•TBI upregulated the expression of STIM2 but not STIM1 in vitro and in vivo.•Knockdown of STIM2 protected against TBI-induced neuronal injury.•Knockdown of STIM2 alleviated TNI-induced calcium overload.•Knockdown of STIM2 alleviated mitochondrial calcium overload and ER calcium release.•Knockdown of STIM2 improved the mitochondrial dynamics and dysfunction.

Although store-operated calcium entry (SOCE) has been implicated in several neurological disorders, the exact mechanism for its role in traumatic brain injury (TBI) has not been elucidated. In this study, we found that TBI upregulated the expression of a calcium sensor protein called stromal interactive molecule 2 (STIM2); however, the levels of its homologue, STIM1, were unaffected. Both STIM1 and STIM2 are crucial components of SOCE, both in vivo and in vitro. Using shRNA, we discovered that downregulation of STIM2, but not STIM1, significantly improved neuronal survival in both an in vitro and in vivo model of TBI, decreasing neuronal apoptosis, and preserving neurological function. This neuroprotection was associated with alleviating TBI-induced calcium overload and preserving mitochondrial function. Additionally, downregulation of STIM2 not only inhibited Ca2 + release from the endoplasmic reticulum (ER), but also reduced SOCE-mediated Ca2 + influx, decreased mitochondrial Ca2 +, restored mitochondrial morphology and improved mitochondrial function, including MMP maintenance, ROS production and ATP synthesis. These results indicate that inhibition of STIM2 can protect neurons from TBI by inhibiting calcium overload and preserving mitochondrial function. This suggests that STIM2 might be an effective interventional target for TBI.