MicroRNA-138 and MicroRNA-25 Down-regulate Mitochondrial Calcium Uniporter, Causing the Pulmonary Arterial Hypertension Cancer Phenotype

Am J Respir Crit Care Med. 2017 Feb 15;195(4):515-529. doi: 10.1164/rccm.201604-0814OC.


Rationale: Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This cancer-like phenotype is promoted by increased cytosolic calcium ([Ca2+]cyto), aerobic glycolysis, and mitochondrial fission.

Objectives: To determine how changes in mitochondrial calcium uniporter (MCU) complex (MCUC) function influence mitochondrial dynamics and contribute to PAH's cancer-like phenotype.

Methods: PASMCs were isolated from patients with PAH and healthy control subjects and assessed for expression of MCUC subunits. Manipulation of the pore-forming subunit, MCU, in PASMCs was achieved through small interfering RNA knockdown or MCU plasmid-mediated up-regulation, as well as through modulation of the upstream microRNAs (miRs) miR-138 and miR-25. In vivo, nebulized anti-miRs were administered to rats with monocrotaline-induced PAH.

Measurements and main results: Impaired MCUC function, resulting from down-regulation of MCU and up-regulation of an inhibitory subunit, mitochondrial calcium uptake protein 1, is central to PAH's pathogenesis. MCUC dysfunction decreases intramitochondrial calcium ([Ca2+]mito), inhibiting pyruvate dehydrogenase activity and glucose oxidation, while increasing [Ca2+]cyto, promoting proliferation, migration, and fission. In PAH PASMCs, increasing MCU decreases cell migration, proliferation, and apoptosis resistance by lowering [Ca2+]cyto, raising [Ca2+]mito, and inhibiting fission. In normal PASMCs, MCUC inhibition recapitulates the PAH phenotype. In PAH, elevated miRs (notably miR-138) down-regulate MCU directly and also by decreasing MCU's transcriptional regulator cAMP response element-binding protein 1. Nebulized anti-miRs against miR-25 and miR-138 restore MCU expression, reduce cell proliferation, and regress established PAH in the monocrotaline model.

Conclusions: These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted.

Keywords: cAMP response element–binding protein; microRNA-25- and -138-5p; mitochondrial calcium uptake protein 1; pyruvate dehydrogenase.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Calcium / metabolism
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism
  • Calcium-Binding Proteins / genetics*
  • Case-Control Studies
  • Cation Transport Proteins / genetics*
  • Cell Culture Techniques / methods
  • Cell Proliferation / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytosol / metabolism
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Genetic Therapy / methods*
  • Glycolysis
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / therapy
  • MicroRNAs / genetics*
  • Mitochondrial Membrane Transport Proteins / genetics*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / pathology*
  • Muscle, Smooth, Vascular / physiopathology
  • Phenotype
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / pathology*
  • Pyruvate Dehydrogenase Complex / metabolism
  • Rats
  • Up-Regulation / genetics


  • Calcium Channels
  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • Cyclic AMP Response Element-Binding Protein
  • MICU1 protein, human
  • MIRN138 microRNA, rat
  • MIRN25 microRNA, human
  • MIRN25 microRNA, rat
  • MicroRNAs
  • Mitochondrial Membrane Transport Proteins
  • Pyruvate Dehydrogenase Complex
  • mitochondrial calcium uniporter
  • Calcium