TGF-β1 attenuates mitochondrial bioenergetics in pulmonary arterial endothelial cells via the disruption of carnitine homeostasis

Xutong Sun, Qing Lu, Manivannan Yegambaram, Sanjiv Kumar, Ning Qu, Anup Srivastava, Ting Wang, Jeffrey R. Fineman, Stephen M. Black

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor beta-1 (TGF-β1) signaling is increased and mitochondrial function is decreased in multiple models of pulmonary hypertension (PH) including lambs with increased pulmonary blood flow (PBF) and pressure (Shunt). However, the potential link between TGF-β1 and the loss of mitochondrial function has not been investigated and was the focus of our investigations. Our data indicate that exposure of pulmonary arterial endothelial cells (PAEC) to TGF-β1 disrupted mitochondrial function as determined by enhanced mitochondrial ROS generation, decreased mitochondrial membrane potential, and disrupted mitochondrial bioenergetics. These events resulted in a decrease in cellular ATP levels, decreased hsp90/eNOS interactions and attenuated shear-mediated NO release. TGF-β1 induced mitochondrial dysfunction was linked to a nitration-mediated activation of Akt1 and the subsequent mitochondrial translocation of endothelial NO synthase (eNOS) resulting in the nitration of carnitine acetyl transferase (CrAT) and the disruption of carnitine homeostasis. The increase in Akt1 nitration correlated with increased NADPH oxidase activity associated with increased levels of p47phox, p67phox, and Rac1. The increase in NADPH oxidase was associated with a decrease in peroxisome proliferator-activated receptor type gamma (PPARγ) and the PPARγ antagonist, GW9662, was able to mimic the disruptive effect of TGF-β1 on mitochondrial bioenergetics. Together, our studies reveal for the first time, that TGF-β1 can disrupt mitochondrial function through the disruption of cellular carnitine homeostasis and suggest that stimulating carinitine homeostasis may be an avenue to treat pulmonary vascular disease.

Original languageEnglish (US)
Article number101593
JournalRedox Biology
Volume36
DOIs
StatePublished - Sep 2020

Keywords

  • Mechanical forces
  • Mitochondrial bioenergetics
  • NADPH oxidase
  • PPARγ
  • ROS
  • TGF-β1

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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