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Series GSE4866 Query DataSets for GSE4866
Status Public on May 18, 2007
Title The role of mtDNA mutations in age-related hearing loss in mice carrying a mutator DNA polymerase gamma
Organism Mus musculus
Experiment type Expression profiling by array
Summary Mitochondrial DNA (mtDNA) mutations may contribute to aging and age-related disorders. Previously, we created mice expressing a proofreading-deficient version of the mtDNA polymerase gamma (Polg) which accumulate age-related mtDNA mutations and display premature aging. Here we performed microarray gene expression profiling to identify mtDNA mutation-responsive genes in the cochlea of aged mitochondrial mutator mice. Age-related accumulation of mtDNA mutations was associated with transcriptional alternations consistent with reduced inner ear function, mitochondrial dysfunction, neurodegeneration, and reduced cell structural modulation. Hearing assessment and histopathological results confirmed that aged PolgD257A/D257A (D257A) mice exhibited moderate hearing loss and severe cochlear degenerations. Age-related accumulation of mtDNA mutations also resulted in alternations in gene expression consistent with induction of apoptosis, proteolysis, stress response, and reduced DNA repair. TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay confirmed that the cochleae from aged D257A mice showed significantly more TUNEL positive cells compared to wild-type (WT) mice. The levels of cleaved caspase-3 were also found to increase in the cochleae of aged D257A mice. These observations provide evidence that age-related accumulation of mtDNA mutations is associated with apoptotic cell death in aged cochlea. Our results provide the first global view of molecular events associated with mtDNA mutations in postmitotic tissue, and suggest that apoptosis is the major mechanism of mtDNA mediated cell death in the development of age-related hearing disorder.
Keywords: disease state analysis
 
Overall design To determine the effects of age-related accumulation of mtDNA mutations, each WT sample (n = 5) was compared to each D257A sample (n = 5), generating a total of twenty-five pairwise comparisons. Genes with significantly altered expression levels were sorted into gene ontology biological process categories.
Gene expression change was called statistically significant when at least one gene was called present in a group, the P value was < 0.0500, FC was > 1.1, and FDR was > 30.00 for identification of mtDNA mutations-induced genes.
Affymetrix standard spike controls were used in all experiments (eukaryotic hybridization control kit). Quality control measures were not used. No replicates were done. Dye swap was not used.
 
Contributor(s) Someya S, Yamasoba T, Kujoth GC, Pugh TD, Weindruch R, Tanokura M, Prolla TA
Citation(s) 17363114
Submission date May 18, 2006
Last update date Feb 11, 2019
Contact name Shinichi Someya
E-mail(s) someya@wisc.edu
Phone 608-265-5205
Fax 608-262-2976
URL http://www.genetics.wisc.edu/faculty/profile.php?id=140
Organization name University of Wisconsin-Madison
Department Medical Genetics
Lab Prolla Lab
Street address 425 Henry Mall Dr
City Madison
State/province WI
ZIP/Postal code 53706
Country USA
 
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (10)
GSM109462 Cochlea_WT_9mo_1
GSM109463 Cochlea_WT_9mo_3
GSM109464 Cochlea_WT_9mo_4
Relations
BioProject PRJNA95755

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE4866_RAW.tar 60.6 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file

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