Identification and characterization of a functional mitochondrial angiotensin system

Abstract

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.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Recently, however, functional GPCRs have also been demonstrated on intracellular membranes including the mitochondria [55] and nuclear envelope (reviewed in [11,14]). The functions of endogenous GPCRs remain to be established.…”

Aging and the Renin-Angiotensin System

“…Of note, chronic administration of losartan prevents an age-related decrease of mitochondrial AT 2 receptors. 48 …”

“…46 The discovery of intramitochondrial angiotensin system provides new insights into the mechanisms contributing to senescence. 48 Functional AT 2 (mitochondrial AT 2 ) receptors are expressed on the mitochondrial inner membrane and colocalize with endogenous Ang II. With age, mitochondrial AT 2 receptor density decreases in renal tubular cells paralleled by increased expression of mitochondrial AT 1 receptors.…”

Pharmarcogenetic Mechanism of ACE I/D Polymorphism Adversely Responding to ACE Inhibitors in Regulating the ACE Promoter Activity in Neurons

“…For instance, Paul et al [44] indicated that "intracellular" ACE converting ANG I to intracellular ANG II in brain neurons may facilitate learning and memory. A functional RAS in mitochondria was demonstrated to have a role in nitric oxide production in many tissues including neurons [45]. Moreover, Bernstein et al recently presented that overexpression of ACE in myelomonocytes could prevent Alzheimer's-like cognitive decline through degrading Aβ and enhancing immunity functions [46].…”