The effect of overexpression of PGC-1α on the mtDNA4834 common deletion in a rat cochlear marginal cell senescence model.

Abstract

Aging is a natural process usually defined as a progressive loss of function with an accumulation of senescent cells. The clinical manifestations of this process include age-related hearing loss (AHL)/presbycusis. Several investigations indicated the association between a mitochondrial common deletion (CD) (mtDNA 4977-bp deletion in humans, corresponding to 4834-bp deletion in rats) and presbycusis. Previous researches have shown that peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a key regulator of mitochondrial biogenesis and energy metabolism. However, the expression of PGC-1α in the inner ear and the possible effect of PGC-1α on presbycusis are not clear. Our data demonstrated the distribution of PGC-1α and its downstream transcription factors nuclear respiratory factor-1 (NRF-1), mitochondrial transcription factor A (Tfam) and nuclear factor κB (NF-κB) in marginal cells (MCs) for the first time. To explore the role of PGC-1α in cellular senescence, we established a model of marginal cell senescence harboring the mtDNA4834 common deletion induced by d-galactose. We also found that PGC-1α and its downstream transcription factors compensatorily increased in our cell senescence model. Furthermore, the overexpression of PGC-1α induced by transfection largely increased the expression levels of NRF-1 and TFAM and significantly decreased the expression level of NF-κB in the cell senescence model. And the levels of CD, senescent cells and apoptotic cells in the cell model decreased after PGC-1α overexpression. These results suggested that PGC-1α might protect MCs in this cell model from senescence through a nuclear-mitochondrial interaction and against apoptosis. Our study may shed light on the pathogenesis of presbycusis and provide a new therapeutic target for presbycusis.

• Authors: Xue-Yan Zhao, Jin-Li Sun, Yu-Juan Hu, Yang Yang, Wen-Juan Zhang, Yuan Hu, Jun Li, Yu Sun, Yi Zhong, Wei Peng, Hong-Lian Zhang, Wei-Jia Kong
• Journal: Hearing research (Hear Res) Vol. 296 Pg. 13-24 (Feb 2013) ISSN: 1878-5891 [Electronic] Netherlands
• PMID: 23159434 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• DNA, Mitochondrial
• NF-kappa B
• Nuclear Respiratory Factor 1
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• RNA-Binding Proteins
• Tfam protein, rat
• Transcription Factors
• Galactose

Topics

• Adenoviridae (genetics)
• Animals
• Animals, Newborn
• Apoptosis
• Cells, Cultured
• Cellular Senescence (drug effects, genetics)
• Cochlea (drug effects, metabolism, pathology)
• DNA, Mitochondrial (genetics)
• Dose-Response Relationship, Drug
• Galactose (pharmacology)
• Genetic Predisposition to Disease
• Genetic Vectors
• NF-kappa B (metabolism)
• Nuclear Respiratory Factor 1 (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Phenotype
• Presbycusis (genetics, metabolism, pathology)
• RNA-Binding Proteins (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sequence Deletion
• Time Factors
• Transcription Factors (genetics, metabolism)
• Transfection
• Up-Regulation