Post-translational decrease in respiratory chain proteins in the Polg mutator mouse brain.

David N Hauser,Allissa A Dillman,Mark R Cookson,Yan Li,Jinhui Ding,Tadafumi Kato

doi:10.1371/journal.pone.0094646

Abstract

Mitochondrial DNA damage is thought to be a causal contributor to aging as mice with inactivating mutations in polymerase gamma (Polg) develop a progeroid phenotype. To further understand the molecular mechanisms underlying this phenotype, we used iTRAQ and RNA-Seq to determine differences in protein and mRNA abundance respectively in the brains of one year old Polg mutator mice compared to control animals. We found that mitochondrial respiratory chain proteins are specifically decreased in abundance in the brains of the mutator mice, including several nuclear encoded mitochondrial components. However, we found no evidence that the changes we observed in protein levels were the result of decreases in mRNA expression. These results show that there are post-translational effects associated with mutations in Polg.

Highlights

Damage to mitochondrial DNA is thought to be central to the process of aging and some age-related diseases [1,2]
Protein samples were labeled with isobaric tags for relative and absolute quantitation 8-plex reagents and analyzed using two separate liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) runs against a pooled reference sample in each run (Fig. 1A)
A gene ontology analysis using DAVID demonstrated that these 1060 proteins were enriched with proteins associated with the cellular component term mitochondrion (n = 289 proteins with GOTERM_CC mitochondrion, Benjamini-Hochberg adjusted p value = 1.8610275) [20]. Statistical analysis of these 1060 proteins revealed that three proteins (NDUS4, Mtco2, and NDUC2) were significantly (P,0.05 after False detective rate (FDR) correction at 5%) decreased in the brains of the polymerase gamma (Polg) mutator mice compared to controls (Fig. 1C)

Summary

Introduction

Damage to mitochondrial DNA (mtDNA) is thought to be central to the process of aging and some age-related diseases [1,2]. Mice homozygous for the mutant allele (Polg D257A/D257A, hereafter termed Polg mutator mice) exhibit a progeroid phenotype with aging phenotypes that include kyphosis, loss of subcutaneous fat, and graying of the hair appearing before one year of age. Polg mutator mice have shortened lifespans with medians of 41 [4] and 59 [3] weeks compared to greater than 2 years reported for wild type mice [3]. The question of whether mtDNA mutations or deletions are the driving force of the progeroid phenotype is unsettled [5,6,7,8,9,10]

Methods

Results

Conclusion