Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans

Cell Metab. 2014 Nov 4;20(5):827-839. doi: 10.1016/j.cmet.2014.08.011. Epub 2014 Oct 2.


Suppression of mitochondrial function promoting proliferation and apoptosis suppression has been described in the pulmonary arteries and extrapulmonary tissues in pulmonary arterial hypertension (PAH), but the cause of this metabolic remodeling is unknown. Mice lacking sirtuin 3 (SIRT3), a mitochondrial deacetylase, have increased acetylation and inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial function. Sirt3KO mice develop spontaneous PAH, exhibiting previously described molecular features of PAH pulmonary artery smooth muscle cells (PASMC). In human PAH PASMC and rats with PAH, SIRT3 is downregulated, and its normalization with adenovirus gene therapy reverses the disease phenotype. A loss-of-function SIRT3 polymorphism, linked to metabolic syndrome, is associated with PAH in an unbiased cohort of 162 patients and controls. If confirmed in large patient cohorts, these findings may facilitate biomarker and therapeutic discovery programs in PAH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cells, Cultured
  • Down-Regulation*
  • Familial Primary Pulmonary Hypertension / genetics
  • Familial Primary Pulmonary Hypertension / pathology
  • Familial Primary Pulmonary Hypertension / therapy
  • Female
  • Genetic Therapy
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / pathology*
  • Hypertension, Pulmonary / therapy
  • Lung / blood supply*
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Polymorphism, Genetic
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Sirtuin 3 / genetics*


  • Sirtuin 3