Age is the greatest risk factor for lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). While LUTS/BPH can be managed with pharmacotherapy, treatment failure has been putatively attributed to numerous pathological features of BPH (e. g., prostatic fibrosis, inflammation). Mitochondrial dysfunction is a hallmark of aging, however its impact on the pathological features of BPH remains unknown.
Publicly available gene array data was analyzed. Immunohistochemistry examined mitochondrial proteins in human prostate. The effect of complex I inhibition (rotenone) on a prostatic cell line was examined using qPCR, immunocytochemistry, and Seahorse assays. Oleic acid was tested as a bypass of complex I inhibition. Aged mice were treated with OA to examine its effects on urinary dysfunction. Voiding was assessed longitudinally, and a critical complex I protein measured.
Mitochondrial function and fibrosis genes were altered in BPH. Essential mitochondrial proteins (i.e., VDAC1/2, PINK1 and NDUFS3) were significantly (P<0.05) decreased in BPH. Complex I inhibition in cultured cells resulted in decreased respiration, altered NDUFS3 expression, increased collagen deposition and gene expression. Oleic acid ameliorated these effects. Oleic acid treated aged mice had significantly (P<0.05) improved voiding function and higher prostatic NDUFS3 expression.
Complex I dysfunction is a potential contributor to fibrosis and lower urinary tract dysfunction in aged mice. Oleic acid partially bypasses complex I inhibition and therefore should be further investigated as a mitochondrial modulator for treatment of LUTS/BPH. Hypotheses generated in this investigation offer a heretofore unexplored cellular target of interest for the management of LUTS/BPH.
The journals of gerontology. Series A, Biological sciences and medical sciences. 2023 Sep 20 [Epub ahead of print]
Alexis E Adrian, Teresa T Liu, Laura E Pascal, Scott R Bauer, Donald B DeFranco, William A Ricke
Department of Urology, George M. O'Brien Center of Research Excellence, University of Wisconsin - Madison, Madison, WI., Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA., Department of Medicine, Urology, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.