Mechanistic and therapeutic role of Drp1 in the pathogenesis of stroke

Abstract

Stroke had emerged as one of the leading causes of death and long-term disability across the globe. Emerging evidence suggests a significant increase in the incidence of stroke with age, which is further expected to increase dramatically owing to an ever-expanding elderly population. The current situation imposes a significant burden on the healthcare system and requires a deeper understanding of the underlying mechanisms and development of novel interventions. It is well established that mitochondrial dysfunction plays a pivotal role in the onset of stroke. Dynamin-related protein 1 (Drp1), is a key regulator of mitochondria fission, and plays a crucial role during the pathogenesis of stroke. Drp1 protein levels significantly increase after stroke potentially in a p38 mitogen-activated protein kinases (MAPK) dependent manner. Protein phosphatase 2A (PP2A) facilitate mitochondrial fission and cell death by dephosphorylating the mitochondrial fission enzyme Drp1 at the inhibitory phosphorylation site serine 637. Outer mitochondrial membrane A-Kinase Anchoring Proteins 1 (AKAP 1) and protein kinase A complex (PKA) complex inhibits Drp1-dependent mitochondrial fission by phosphorylating serine 637. Drp1 activation promotes the release of cytochrome C from mitochondria and therefore leads to apoptosis. In addition, Drp1 activation inhibits mitochondrial glutathione dependent free radical scavenging, which further enhances the ROS level and exacerbate mitochondrial dysfunction. Drp1 translocate p53 to mitochondrial membrane and leads to mitochondria-related necrosis. The current review article discusses the possible mechanistic pathways by which Drp1 can influence the pathogenesis of stroke. Besides, it will describe various inhibitors for Drp1 and their potential role as therapeutics for stroke in the future.