Cerebral ischemia-reperfusion is modulated by macrophage-stimulating 1 through the MAPK-ERK signaling pathway.

Cerebral ischemia-reperfusion (IR) injury is associated with mitochondrial damage. Macrophage-stimulating 1 (MST1) reportedly stimulates mitochondrial apoptosis by suppressing BCL-2. We investigated whether MST1 promotes the progression of cerebral IR injury by inducing mitochondrial dysfunction in vivo and in vitro. Western blot analysis, quantitative polymerase chain reaction, immunofluorescence, and mitochondrial function assays were conducted in cells from wild-type and Mst1-knockout mice subjected to cerebral IR injury. MST1 expression in wild-type glial cells increased following cerebral IR injury. Cerebral IR injury reduced the mitochondrial membrane potential and mitochondrial metabolism in glial cells, while it enhanced mitochondrial reactive oxygen species generation and mitochondrial calcium levels in these cells. The deletion of Mst1 attenuated cerebral IR injury by improving mitochondrial function and reducing mitochondrial damage. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway was suppressed in wild-type glial cell upon cerebral IR injury but was reactivated in Mst1-knockout glial cell. Accordingly, blocking the MAPK/ERK pathway abolished the beneficial effects of Mst1 deletion during cerebral IR injury by inducing mitochondrial damage in glial cells. Our results suggest that cerebral IR injury is associated with MST1 upregulation in the brain, while the genetic ablation of Mst1 can attenuate mitochondrial damage and sustain brain function following cerebral IR injury.