Mitochondrial Feedback Mechanisms in Kidney Cell Senescence

Abstract

Background

Progressive DNA damage (telomere attrition) is considered one of the key instigators of ageing. Different models for ageing where DNA damage leads to accelerated senescence have been proposed.

Methods

A test cohort of 40 consecutive kidney donors, with pre-implantation renal allograft biopsies, was included in this study. All biopsies were rescored according to the Banff classification. Intrarenal and donor leucocyte telomere length, and mitochondrial DNA content was assessed using quantitative RT-PCR. In these same samples (N=40), whole genome microarray mRNA expression analysis was performed using Affymetrix Gene 2.0 ST arrays (N=40). The associations between mRNA gene expression and the biomarkers of replicative senescence were investigated using multiple regression models, adjusted for calendar age, gender and batch number. For biological interpretation, Ingenuity Pathway Analysis and Consensus software were used to identify overrepresented pathways. An independent cohort of 160 implantation biopsies was used for validation.

Results

In total, 1180 transcripts significantly associated with intrarenal telomere length, of which 611 were significantly upregulated with shorter telomeres. Pathway analysis revealed enrichment of transcripts coding for proteins of the citric acid cycle (q=1.06×10-13), transcripts involved in respiratory electron transport (q=1.06×10-13) and transcripts involved in oxidative phosphorylation (q=4.48×0-10). Also mitochondrial DNA content correlated highly significantly with telomere length (r= 0.3; p=0.0005). Independent replication of these findings is on-going on a separate cohort of 160 pre-implantation biopsies.

Conclusion

This unbiased study suggests that mitochondrial alterations (DNA content and mitochondrial gene expression) are key features of replicative senescence of human kidneys. Upregulation of mitochondrial gene expression in baseline kidneys for transplantation is a protective feedback mechanism and a potential therapeutic target for improving renal allograft viability in the perioperative phase.