Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter

Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9096-E9104. doi: 10.1073/pnas.1711303114. Epub 2017 Oct 9.


Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2-/- mice. Mutant mice had left atrial enlargement and Micu2-/- cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2-/- ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (Micu2-/- vs. wild type, P = 7.8 × 10-40), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that Micu2-/- and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that Micu2-/- mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from Micu2-/- mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that Micu2-/- mice recapitulate features of diastolic heart disease and define previously unappreciated roles for Micu2 in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.

Keywords: aortic aneurysms; calcium; diastolic dysfunction; hypertension; mitochondrial calcium uniporter.

Publication types

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

MeSH terms

  • Angiotensin Amide / genetics
  • Angiotensin II / pharmacology
  • Animals
  • Aorta, Abdominal / pathology
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cardiomyopathy, Hypertrophic, Familial / genetics*
  • Cardiomyopathy, Hypertrophic, Familial / pathology
  • Electrocardiography
  • Gene Expression Regulation
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Humans
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mitochondria, Liver / physiology
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology


  • Calcium Channels
  • Calcium-Binding Proteins
  • MICU2 protein, human
  • Micu2 protein, mouse
  • Angiotensin II
  • Angiotensin Amide
  • Calcium