Examining the role of defective oxidative phosphorylation in the normal and diseased prostate

ABSTRACT Lower urinary tract symptoms (LUTS) are a significant burden to aging men and are often as a result of benign prostatic hyperplasia (BPH). While BPH/LUTS is not commonly fatal with proper medical intervention, it does cause a significant reduction in quality of life for many men as they age. Furthermore, BPH/LUTS increases risk of mortality and results in billions of dollars in healthcare costs annually. There is currently a subset of BPH/LUTS patients that fail FDA-approved treatments (α-blockers, 5ARI), and these patients have been shown to have increased prostatic fibrosis. There is no FDA-approved medication targeting fibrosis or the aging process in BPH/LUTS, even though aging is the greatest risk factor. This proposal aims to develop a better understanding about the role of aging, fibrosis, and mitochondrial dysfunction in BPH/LUTS. Mitochondrial dysfunction is a hallmark of both aging and fibrosis and has not been thoroughly studied in relation to BPH/LUTS. Preliminary data suggests that oxidative phosphorylation (OXPHOS) is a mitochondrial pathway contributing to cellular dysfunction in BPH/LUTS. Aim 1 of this proposal intends to investigate the connection between OXPHOS disruption and lower urinary tract dysfunction (LUTD) in a novel mouse model. Aim 2 of this proposal will investigate the connection between OXPHOS disruption and pathways associated with fibrosis, using genetic loss-of-function cell line models. Finally, Aim 3 will work to identify a new pathway of interest for treatment, using oleic acid as a mitochondrial metabolism modulator. Collectively, these aims will improve our overall understanding of the processes underlying BPH/LUTS, with a special focus on aging, mitochondrial dysfunction, and fibrosis. This proposal hopes to provide translational outcomes that can eventually improve patient care and treatment options.