Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission

J Biol Chem. 2023 Apr;299(4):103067. doi: 10.1016/j.jbc.2023.103067. Epub 2023 Feb 24.

Abstract

Mitochondrial fission and a Warburg phenotype of increased cellular glycolysis are involved in the pathogenesis of pulmonary hypertension (PH). The purpose of this study was to determine whether increases in mitochondrial fission are involved in a glycolytic switch in pulmonary arterial endothelial cells (PAECs). Mitochondrial fission is increased in PAEC isolated from a sheep model of PH induced by pulmonary overcirculation (Shunt PAEC). In Shunt PAEC we identified increases in the S616 phosphorylation responsible for dynamin-related protein 1 (Drp1) activation, the mitochondrial redistribution of Drp1, and increased cellular glycolysis. Reducing mitochondrial fission attenuated cellular glycolysis in Shunt PAEC. In addition, we observed nitration-mediated activation of the small GTPase RhoA in Shunt PAEC, and utilizing a nitration-shielding peptide, NipR1 attenuated RhoA nitration and reversed the Warburg phenotype. Thus, our data identify a novel link between RhoA, mitochondrial fission, and cellular glycolysis and suggest that targeting RhoA nitration could have therapeutic benefits for treating PH.

Keywords: ROS; endothelial cell; mitochondrial bioenergetics; mitochondrial fission; pulmonary hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dynamins* / metabolism
  • Endothelial Cells / metabolism
  • Glycolysis*
  • Hypertension, Pulmonary* / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Dynamics* / genetics
  • Monomeric GTP-Binding Proteins* / metabolism
  • Sheep
  • rhoA GTP-Binding Protein*

Substances

  • Dynamins
  • Monomeric GTP-Binding Proteins
  • rhoA GTP-Binding Protein