Activation of mitochondrial angiotensin II type 2 receptors stimulates nitric oxide production and modulates respiration, while age-related declines in these receptors are reversed by losartan.
This study provides the first evidence of a functional mitochondrial angiotensin system that regulates nitric oxide production and respiration, revealing a novel subcellular target for RAS modulators.
Absolute Event Rate: 0.6% vs 0.52%
p-value: p=<0.001
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.
Abadir et al. (Thu,) conducted a other in Mitochondrial function and aging. AT2R agonist (CGP421140) and AT1R blocker (losartan) vs. Baseline/Control or untreated was evaluated on Mitochondrial NO production (fluorescence arbitrary units) (p=<0.001). Activation of mitochondrial angiotensin II type 2 receptors stimulates nitric oxide production and modulates respiration, while age-related declines in these receptors are reversed by losartan.