Laboratory of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China.
Department of Neurology, Affiliated Hospital of Hebei University, Baoding 071000, China.
Oxid Med Cell Longev. 2022 Feb 18;2022:3644318. doi: 10.1155/2022/3644318. eCollection 2022.
Reduced testosterone level is a common feature of aging in men. Aging, as a risk factor for several neurodegenerative disorders, shows declined mitochondrial function and downregulated mitochondrial biogenesis and mitochondrial dynamics. Mitochondrial biogenesis and mitochondrial dynamics are crucial in maintaining proper mitochondrial function. Supplementation with testosterone is conducive to improving mitochondrial function of males during aging. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of redox homeostasis, is involved in the ameliorative effects of testosterone supplementation upon aging. To explore Nrf2 role in the effects of testosterone supplementation on mitochondrial function during aging, we studied the efficiency of testosterone supplementation in improving mitochondrial function of Nrf2 knockout- (KO-) aged male mice by analyzing the changes of mitochondrial biogenesis and mitochondrial dynamics. It was found that wild-type- (WT-) aged male mice showed low mitochondrial function and expression levels of PGC-1, NRF-1\NRF-2, and TFAM regulating mitochondrial biogenesis, as well as Drp1, Mfn1, and OPA1 controlling mitochondrial dynamics in the substantia nigra (SN). Nrf2 KO aggravated the defects above in SN of aged male mice. Testosterone supplementation to WT-aged male mice significantly ameliorated mitochondrial function and upregulated mitochondrial biogenesis and mitochondrial dynamics, which were not shown in Nrf2 KO-aged male mice due to Nrf2 deficiency. Testosterone deficiency by gonadectomy (GDX) decreased mitochondrial function, downregulated mitochondrial biogenesis, and altered mitochondrial dynamics balance in young male mice. Supplementation with testosterone to Nrf2 KO-GDX mice only ameliorated the alterations above but did not reverse them to sham level. Nrf2 deficiency attenuated testosterone efficiency in ameliorating mitochondrial function in the SN of aged male mice through mitochondrial biogenesis and mitochondrial dynamics to some extent. Activation of Nrf2 might contribute to testosterone-upregulating mitochondrial biogenesis and mitochondrial dynamics in the SN during aging to produce efficient mitochondria for ATP production.
睾酮水平降低是男性衰老的一个常见特征。衰老作为几种神经退行性疾病的风险因素，表现为线粒体功能下降、线粒体生物发生和线粒体动力学下调。线粒体生物发生和线粒体动力学对于维持适当的线粒体功能至关重要。睾酮补充有利于改善衰老过程中男性的线粒体功能。核因子红细胞 2 相关因子 2（Nrf2）是氧化还原平衡的调节剂，参与了睾酮补充对衰老的改善作用。为了探讨 Nrf2 在睾酮补充对衰老过程中线粒体功能影响中的作用，我们通过分析线粒体生物发生和线粒体动力学的变化，研究了睾酮补充对 Nrf2 敲除（KO）衰老雄性小鼠改善线粒体功能的效率。结果发现，野生型（WT）衰老雄性小鼠表现出低线粒体功能和调节线粒体生物发生的 PGC-1、NRF-1/NRF-2 和 TFAM 的表达水平，以及控制线粒体动力学的 Drp1、Mfn1 和 OPA1 在黑质（SN）中的表达水平降低。Nrf2 KO 加剧了衰老雄性小鼠 SN 中的上述缺陷。睾酮补充到 WT 衰老雄性小鼠中显著改善了线粒体功能，并上调了线粒体生物发生和线粒体动力学，而由于 Nrf2 缺乏，Nrf2 KO 衰老雄性小鼠中未显示出这些变化。性腺切除术（GDX）导致雄性小鼠的睾丸酮缺乏，降低了线粒体功能，下调了线粒体生物发生，并改变了年轻雄性小鼠的线粒体动力学平衡。补充睾丸酮到 Nrf2 KO-GDX 小鼠中仅改善了上述变化，但未能将其逆转至假手术水平。Nrf2 缺乏在一定程度上减弱了睾酮在改善衰老雄性小鼠 SN 中线粒体功能方面的作用，通过线粒体生物发生和线粒体动力学。Nrf2 的激活可能有助于睾酮在衰老过程中上调 SN 中线粒体生物发生和线粒体动力学，以产生用于 ATP 产生的有效线粒体。
