Succinate Promotes Stem Cell Migration Through the GPR91-dependent Regulation of DRP1-mediated Mitochondrial Fission

Sci Rep. 2017 Oct 3;7(1):12582. doi: 10.1038/s41598-017-12692-x.

Abstract

The role of metabolites produced from stem cell metabolism has been emerged as signaling molecules to regulate stem cell behaviors such as 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, we investigate the effect of succinate on hMSC migration via regulation of mitochondrial dynamics and its related signaling pathway. Succinate (50 μM) significantly accelerates hMSC migration. Succinate increases phosphorylation of pan-PKC, especially the atypical PKCζ level which was blocked by the knockdown of Gαq and Gα12. Activated PKCζ subsequently phosphorylates p38 MAPK. Cytosolic DRP1 is phosphorylated by p38 MAPK and results in DRP1 translocation to the mitochondria outer membrane, eventually inducing mitochondrial fragmentation. Mitochondrial fission-induced mitochondrial function elevates mitochondrial ROS (mtROS) levels and activates Rho GTPases, which then induces F-actin formation. Furthermore, in a skin excisional wound model, we found the effects of succinate-pretreated hMSC enhanced wound closure, vascularization and re-epithelialization and confirmed that DRP1 has a vital role in injured tissue regeneration. Overall, succinate promotes DRP1-mediated mitochondrial fission via GPR91, consequently stimulating the hMSC migration through mtROS-induced F-actin formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actins / genetics
  • Autophagy / drug effects
  • Cell Movement / genetics
  • Cytosol / drug effects
  • GTP Phosphohydrolases / genetics*
  • Gene Expression Regulation / drug effects
  • Humans
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / metabolism
  • Microtubule-Associated Proteins / genetics*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / drug effects*
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Proteins / genetics*
  • Phosphorylation / drug effects
  • Protein Binding / genetics
  • Receptors, G-Protein-Coupled / genetics*
  • Signal Transduction / drug effects
  • Succinic Acid / metabolism*
  • Succinic Acid / pharmacology
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Actins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Receptors, G-Protein-Coupled
  • SUCNR1 protein, human
  • Succinic Acid
  • p38 Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • DNM1L protein, human