Division of Geriatric Medicine and Gerontology, Biology of Healthy Aging Program, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14849-54. doi: 10.1073/pnas.1101507108. Epub 2011 Aug 18.
The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.
肾素-血管紧张素（Ang）系统通过血管紧张素 II 型 1 和 2 型受体调节多种生理功能。先前的研究表明，Ang II 可能存在细胞内池，在拉伸时以自分泌方式释放，以激活表面膜 Ang 受体。或者，已经提出了细胞内肾素-血管紧张素系统，主要关注核 Ang 受体。以前没有描述过线粒体血管紧张素系统。在这里，我们报告功能性血管紧张素 II 型 2 受体存在于线粒体内膜上，并与内源性 Ang 共定位。我们证明，线粒体血管紧张素系统的激活与线粒体一氧化氮的产生偶联，并可以调节呼吸。此外，我们提供了与年龄相关的线粒体 Ang 受体表达变化的证据，即增加的线粒体血管紧张素 II 型 1 受体和减少的 2 型受体密度，用血管紧张素 II 型 1 受体阻滞剂氯沙坦进行慢性治疗可逆转这种变化。功能性 Ang 系统在人线粒体中的存在为理解线粒体与慢性疾病状态之间的相互作用提供了基础，并揭示了优化线粒体功能和减少衰老相关慢性疾病负担的潜在治疗靶点。
