The role of succinate-induced DRP1-mediated mitochondrial fission in human mesenchymal stem cell migration

Abstract

The roles of metabolites produced from stem cell metabolism alterations have been emerging as signaling molecules to regulate stem cell behaviors such as proliferation and migration. The mitochondrial morphology is closely associated with the metabolic balance and stem cell function. However, the physiological role of succinate on human mesenchymal stem cell (hMSC) migration by regulating the mitochondrial morphology remains unclear. Here, I investigate the underlying mechanism of succinate on the regulation of mitochondrial dynamic proteins and subsequent hMSC migration. Succinate (50 μM) significantly accelerated hMSC migration, which was inhibited by succinate receptor1 (gpr91) siRNA transfection. Succinate increased phosphorylation of pan-PKC, especially the atypical PKCζ level which was blocked by the knockdown of Gαq and Gα12. Activated PKCζ subsequently phosphorylated p38 MAPK, which was inhibited by staurosporine. Cytosolic DRP1 was phosphorylated by p38 MAPK and results in DRP1 translocation to the mitochondria outer membrane, eventually inducing mitochondrial fission. After mitochondrial fission, succinate increased ATP levels, the mitochondrial membrane potential (Δψm), and mitochondrial ROS (mtROS) and they were attenuated by drp1 gene silencing. Subsequently, the elevated mtROS levels activated Rho GTPases and induced F-actin formation. Furthermore, in a skin excisional wound model, I found effects of succinate-pretreated hMSC enhanced wound closure, vascularization and re-epithelialization which were attenuated by the silencing of drp1. In conclusion, succinates promote DRP1-mediated mitochondrial fission via GPR91-dependent PKCζ/p38 MAPK activation which stimulates hMSC migration through mtROS/Rho GTPase-induced F-actin formation.