Cystathionine beta synthase regulates mitochondrial dynamics and function in endothelial cells

FASEB J. 2020 Jul;34(7):9372-9392. doi: 10.1096/fj.202000173R. Epub 2020 May 28.

Abstract

Mutations in the human cystathionine beta synthase (CBS) gene are known to cause endothelial dysfunction responsible for cardiovascular and neurovascular diseases. CBS is the predominant hydrogen sulfide (H2 S)-producing enzyme in endothelial cells (ECs). Recently, H2 S was shown to attenuate ROS and improve mitochondrial function. Mitochondria are metabolic organelles that actively transform their ultrastructure to mediate their function. Therefore, we questioned whether perturbation of CBS/H2 S activity could drive mitochondrial dysfunction via mitochondrial dynamics in ECs. Here we demonstrate that silencing CBS induces mitochondria fragmentation, attenuates efficient oxidative phosphorylation, and decreases EC function. Mechanistically, CBS silencing significantly elevates ROS production, thereby leading to reduced mitofusin 2 (MFN2) expression, decouple endoplasmic reticulum-mitochondria contacts, increased mitochondria fission, enhanced receptor-mediated mitophagy, and increased EC death. These defects were significantly rescued by the treatment of H2 S donors. Taken together our data highlights a novel signaling axis that mechanistically links CBS with mitochondrial function and ER-mitochondrial tethering and could be considered as a new therapeutic approach for the intervention of EC dysfunction-related pathologies.

Keywords: endothelial cells; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cells, Cultured
  • Cystathionine beta-Synthase / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology*
  • Humans
  • Mitochondria / physiology*
  • Mitochondrial Dynamics*
  • Mitophagy*
  • Oxidative Stress*
  • Signal Transduction

Substances

  • Cystathionine beta-Synthase