title: 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.
authors.affiliation: Division of Geriatric Medicine and Gerontology, Biology of Healthy Aging Program, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Abadir
authors.forename: D Brian
authors.initials: DB
authors.lastname: Foster
authors.forename: Michael
authors.initials: M
authors.lastname: Crow
authors.forename: Carol A
authors.initials: CA
authors.lastname: Cooke
authors.forename: Jasma J
authors.initials: JJ
authors.lastname: Rucker
authors.forename: Alka
authors.initials: A
authors.lastname: Jain
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Tyesha N
authors.initials: TN
authors.lastname: Burks
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Cohn
authors.forename: Neal S
authors.initials: NS
authors.lastname: Fedarko
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002908:Chronic Disease; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D009569:Nitric Oxide; D019808:Losartan