Androgen receptor (AR) signaling plays a central role in metabolic reprogramming for prostate cancer (PCa) growth and progression. Mitochondria are metabolic powerhouses of the cell and support several hallmarks of cancer. However, the molecular links between AR signaling and the mitochondria that support the metabolic demands of PCa cells are poorly understood. Here, we demonstrate increased levels of dynamin-related protein 1 (DRP1), a mitochondrial fission mediator, in androgen-sensitive and castration-resistant AR-driven PCa. AR signaling upregulates DRP1 to form the VDAC-MPC2 complex, increases pyruvate transport into mitochondria, and supports mitochondrial metabolism, including oxidative phosphorylation and lipogenesis. DRP1 inhibition activates the cellular metabolic stress response, which involves AMPK phosphorylation, induction of autophagy, and the ER unfolded protein response, and attenuates androgen-induced proliferation. Additionally, DRP1 expression facilitates PCa cell survival under diverse metabolic stress conditions, including hypoxia and oxidative stress. Moreover, we found that increased DRP1 expression was indicative of poor prognosis in patients with castration-resistant PCa. Collectively, our findings link androgen signaling-mediated mitochondrial dynamics to metabolic reprogramming; moreover, they have important implications for understanding PCa progression.

中文翻译：

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雄激素诱导的DRP1表达调节前列腺癌中的线粒体代谢重编程。

雄激素受体（AR）信号传导在前列腺癌（PCa）生长和进展的代谢重编程中起着核心作用。线粒体是细胞的代谢动力，支持多种癌症特征。但是，AR信号和支持PCa细胞代谢需求的线粒体之间的分子联系了解得很少。在这里，我们证明了雄激素敏感性和去势抵抗性AR驱动的PCa中，与动蛋白有关的蛋白1（DRP1）（一种线粒体裂变介体）的水平提高了。AR信号转导上调DRP1形成VDAC-MPC2复合物，增加丙酮酸向线粒体的转运，并支持线粒体代谢，包括氧化磷酸化和脂肪生成。DRP1抑制可激活细胞代谢应激反应，其中涉及AMPK磷酸化，诱导自噬，ER展开蛋白反应，并减弱雄激素诱导的增殖。此外，DRP1表达有助于PCa细胞在多种代谢应激条件下生存，包括缺氧和氧化应激。此外，我们发现，去势抵抗型PCa患者的DRP1表达增加预后不良。总的来说，我们的发现将雄激素信号介导的线粒体动力学与代谢重编程联系起来。此外，它们对于理解PCa进程具有重要意义。我们发现，去势抵抗性PCa患者的DRP1表达增加预后不良。总的来说，我们的发现将雄激素信号介导的线粒体动力学与代谢重编程联系起来。此外，它们对于理解PCa进程具有重要意义。我们发现，去势抵抗性PCa患者的DRP1表达增加预后不良。总的来说，我们的发现将雄激素信号介导的线粒体动力学与代谢重编程联系起来。此外，它们对于理解PCa进程具有重要意义。