Endoplasmic Reticulum Stress Pathway Activation in Prostate Cancer

Grants and Contracts Details

Description

Mitchondrial alterations accumulate with age and have been suggested to lead to mitochondrial and cellular dysfunction, possibly contributing to senescence and late life diseases. Evidence in support of this theory comes from the identification of mitchondrial DNA (mtDNA) mutations which accumulate with age in human and rodent post-mitotic tissues. The total pool of mutated mtDNA genomes is very low «0.1 %), leading many investigators to question their importance. Using a PCR-based assay and fiber bundle analysis of rhesus monkey skeletal muscle, these mutations were found to not be distributed evenly, but rather were localized to specific cells. Furthermore, their abundance within subsets of cells was found to be markedly higher, suggesting these mutations can accumulate to high levels within a single cell, possibly contributing to sarcopenia. To gain insight into the mechanism of age-related changes in mitochondrial function, D. melanogaster was used. In this model, mtDNA deletions were not associated with aging. However, numerous changes in mitochondrial function and gene expression were detected. The activity of several electron transport system complexes was measured, and declines were observed for only cytochrome oxidase (COX). To detemine the factors contributing to this activity, the abundance of mitochondrial transcripts for COX subunits was measured with molecular and histochemical techniques. A 5-10 fold decline in message was observed with age. Oxidative stress is inversely related to longevity in this model. Analysis of antioxidant mutant and hydrogen peroxide treated flies showed that oxidative stress led to preferential reductions in mitochondrial RNA and COX activity. These studies demonstrated that oxidative stress is closely associated with reductions in mitcochondrial transcript levels, and support the hypothesis that oxidative stress may contribute to mitochondrial dysfunction and aging in D. melanogaster.
StatusFinished
Effective start/end date7/1/076/30/09

Funding

  • New York Academy of Medicine: $80,000.00