NARP mutation and mtDNA depletion trigger mitochondrial biogenesis which can be modulated by selenite supplementation

Int J Biochem Cell Biol. 2011 Aug;43(8):1178-86. doi: 10.1016/j.biocel.2011.04.011. Epub 2011 Apr 28.


The importance of mitochondrial biogenesis in the pathogenesis of mitochondrial diseases has been widely recognised but little is known about it with regard to NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) syndrome. Since such knowledge would contribute to the understanding of the pathogenesis of this disease, we designed a study to provide comprehensive overview of mitochondrial biogenesis in cybrid cells harboring NARP mutation (8993T>G). We also used Rho0 cells with the same nuclear background to show that distinct mtDNA defects lead to distinct cellular responses irrespective of nuclear genome. Mitochondrial biogenesis is regulated by mitochondria-to-nucleus (retrograde) communication which depends on intracellular signaling pathways sensitive to ROS. Since we previously found that selenite lowered ROS in NARP cybrids, we hypothesised that selenite could also modulate mitochondrial biogenesis in these cells. Although the mitochondrial mass was not changed in NARP cybrids, we showed the compensatory upregulation of respiratory chain subunits which prompted us to investigate the transcription factors that regulate their expression such as PGC-1α, NRFs, and TFAM. Selenite supplementation increased the level of NRF1 and nuclear accumulation of NRF2, but we did not detect any major changes in the levels of investigated respiratory chain proteins. These subtle changes in mitochondrial biogenesis in response to selenite treatment support the hypothesis that selenite could be considered as a potential therapeutic agent of NARP syndrome due to its antioxidant properties. Moreover, it could also be tested with regard to other mitochondrial disorders associated with ROS overproduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cells, Cultured
  • Cytochromes c / metabolism
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dietary Supplements
  • Fibroblasts / pathology
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Ion Channels / metabolism
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondrial Myopathies / drug therapy*
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Myopathies / metabolism
  • Mitochondrial Myopathies / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mutation*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphorylation
  • Retinitis Pigmentosa / drug therapy*
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / metabolism
  • Retinitis Pigmentosa / pathology
  • Sodium Selenite / administration & dosage*
  • Transcription Factors / metabolism
  • Uncoupling Protein 3


  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Ion Channels
  • Mitochondrial Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors
  • Uncoupling Protein 3
  • Cytochromes c
  • Sodium Selenite

Supplementary concepts

  • Neuropathy ataxia and retinitis pigmentosa