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Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness.

Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming from primary defects in respiration, coupled with altered reactive oxygen species (ROS), metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally inherited deafness disrupts mitochondrial ribosome function, in part, via increased methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patient-derived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent hearing loss. This mouse mitochondrial disease model provides a robust platform for deciphering the complex tissue specificity of human mitochondrial-based disorders, as well as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by environmental factors.

Pubmed ID: 22341444


  • Raimundo N
  • Song L
  • Shutt TE
  • McKay SE
  • Cotney J
  • Guan MX
  • Gilliland TC
  • Hohuan D
  • Santos-Sacchi J
  • Shadel GS



Publication Data

February 17, 2012

Associated Grants

  • Agency: NIDCD NIH HHS, Id: R01 DC000273
  • Agency: NIDCD NIH HHS, Id: R01 DC000273
  • Agency: NIDCD NIH HHS, Id: R01 DC000273-30
  • Agency: NHLBI NIH HHS, Id: R01 HL-059655
  • Agency: NHLBI NIH HHS, Id: R01 HL059655
  • Agency: NHLBI NIH HHS, Id: R01 HL059655-13

Mesh Terms

  • Animals
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Deafness
  • Disease Models, Animal
  • E2F1 Transcription Factor
  • Ear, Inner
  • Ganglion Cysts
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitochondria
  • Mitochondrial Proteins
  • Mutation
  • Neurons
  • RNA, Ribosomal
  • Reactive Oxygen Species
  • Signal Transduction
  • Transcription Factors