TY - JOUR
T1 - Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness
AU - Raimundo, Nuno
AU - Song, Lei
AU - Shutt, Timothy E.
AU - McKay, Sharen E.
AU - Cotney, Justin
AU - Guan, Min Xin
AU - Gilliland, Thomas C.
AU - Hohuan, David
AU - Santos-Sacchi, Joseph
AU - Shadel, Gerald S.
N1 - Funding Information:
This study was supported by grants R01 HL-059655 to G.S.S. and R01 DC000273 to J.S.-S. from the U.S. NIH and a UMDF fellowship to T.E.S. The authors thank Zimei Zhang for animal husbandry, Yale Animal Genomic Services for help in generating the Tg-mtTFB1 mice, and Dr. Susan Kaech for comments on the manuscript, helpful discussions and access to the SeaHorse instrument.
PY - 2012/2/17
Y1 - 2012/2/17
N2 - 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. PaperFlick:
AB - 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. PaperFlick:
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U2 - 10.1016/j.cell.2011.12.027
DO - 10.1016/j.cell.2011.12.027
M3 - Article
C2 - 22341444
AN - SCOPUS:84857343794
VL - 148
SP - 716
EP - 726
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -