Department of Urology, George M. O'Brien Center of Research Excellence, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Gerontol A Biol Sci Med Sci. 2024 Jun 1;79(6). doi: 10.1093/gerona/glad222.
Age is the greatest risk factor for lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). Although LUTS/BPH can be managed with pharmacotherapy, treatment failure has been putatively attributed to numerous pathological features of BPH (eg, 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 were analyzed. Immunohistochemistry examined mitochondrial proteins in the human prostate. The effect of complex I inhibition (rotenone) on a prostatic cell line was examined using quantitative polymerase chain reaction, immunocytochemistry, and Seahorse assays. Oleic acid (OA) 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 (ie, voltage-dependent anion channels 1 and 2, PTEN-induced kinase 1, and NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial [NDUFS3]) were significantly (p < .05) decreased in BPH. Complex I inhibition in cultured cells resulted in decreased respiration, altered NDUFS3 expression, increased collagen deposition, and gene expression. OA ameliorated these effects. OA-treated aged mice had significantly (p < .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. OA 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.
年龄是良性前列腺增生（BPH）导致下尿路症状（LUTS/BPH）的最大风险因素。虽然 LUTS/BPH 可以通过药物治疗来控制，但治疗失败据称归因于 BPH 的许多病理特征（例如前列腺纤维化、炎症）。线粒体功能障碍是衰老的标志；然而，其对 BPH 病理特征的影响尚不清楚。
分析了公开的基因阵列数据。免疫组织化学检查了人前列腺中的线粒体蛋白。使用定量聚合酶链反应、免疫细胞化学和 Seahorse 测定法检查了对前列腺细胞系的复合物 I 抑制（鱼藤酮）的影响。测试油酸（OA）作为复合物 I 抑制的旁路。用 OA 治疗老年小鼠，以检查其对尿功能障碍的影响。纵向评估排尿功能，并测量关键的复合物 I 蛋白。
BPH 中改变了线粒体功能和纤维化基因。重要的线粒体蛋白（即电压依赖性阴离子通道 1 和 2、PTEN 诱导的激酶 1 和 NADH 脱氢酶 [泛醌] 铁硫蛋白 3、线粒体 [NDUFS3]）在 BPH 中显著（p<0.05）降低。培养细胞中的复合物 I 抑制导致呼吸减少、NDUFS3 表达改变、胶原蛋白沉积增加和基因表达改变。OA 改善了这些影响。OA 治疗的老年小鼠排尿功能明显改善（p<0.05），前列腺 NDUFS3 表达升高。
复合物 I 功能障碍是老年小鼠纤维化和下尿路功能障碍的潜在原因。OA 部分绕过复合物 I 抑制，因此应作为治疗 LUTS/BPH 的线粒体调节剂进一步研究。本研究中提出的假设为 LUTS/BPH 的管理提供了一个迄今为止尚未探索的细胞靶标。
