Mitochondrial pore opening and loss of Ca2+ exchanger NCLX levels occur after frataxin depletion

Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):618-631. doi: 10.1016/j.bbadis.2017.12.005. Epub 2017 Dec 6.

Abstract

Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons. In cardiomyocytes, frataxin depletion also results in mitochondrial permeability transition pore opening. Since the pore opening can be inhibited by cyclosporin A, we show that this treatment reduces lipid droplets and mitochondrial swelling in cardiomyocytes, restores DRG neuron survival and inhibits NFAT dephosphorylation. These results highlight the importance of calcium homeostasis and that targeting mitochondrial pore by repurposing cyclosporin A, could be envisaged as a new strategy to treat the disease.

Keywords: Cyclosporin A; Frataxin; Mitochondrial permeability transition pore (MPTP); NCLX; NFAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Calcineurin / chemistry
  • Calcium / metabolism*
  • Cell Survival
  • Cyclosporine / chemistry
  • Disease Models, Animal
  • Frataxin
  • Friedreich Ataxia / metabolism
  • Ganglia, Spinal / metabolism
  • Iron-Binding Proteins / chemistry*
  • Lipids / chemistry
  • Lymphocytes / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria, Heart / physiology*
  • Mitochondrial Membrane Transport Proteins / chemistry
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Membrane Transport Proteins / physiology*
  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Swelling / drug effects
  • Myocytes, Cardiac / metabolism
  • NFATC Transcription Factors / metabolism*
  • Neurons / metabolism
  • Permeability
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Calcium Exchanger / chemistry
  • Sodium-Calcium Exchanger / metabolism*

Substances

  • Iron-Binding Proteins
  • Lipids
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • NFATC Transcription Factors
  • Slc8b1 protein, rat
  • Sodium-Calcium Exchanger
  • Cyclosporine
  • Calcineurin
  • Calcium