title: No evidence for a local renin-angiotensin system in liver mitochondria.
abstract: The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.
authors: 1] Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, United Kingdom [2] Institute for Human Health and Performance, University College London, London, United Kingdom.
authors: Ronan
authors: R
authors: Astin
authors: Robert
authors: R
authors: Bentham
authors: Siamak
authors: S
authors: Djafarzadeh
authors: James A
authors: JA
authors: Horscroft
authors: Rhoda E
authors: RE
authors: Kuc
authors: Po Sing
authors: PS
authors: Leung
authors: James R A
authors: JR
authors: Skipworth
authors: Jose M
authors: JM
authors: Vicencio
authors: Anthony P
authors: AP
authors: Davenport
authors: Andrew J
authors: AJ
authors: Murray
authors: Jukka
authors: J
authors: Takala
authors: Stephan M
authors: SM
authors: Jakob
authors: Hugh
authors: H
authors: Montgomery
authors: Gyorgy
authors: G
authors: Szabadkai
mesh_terms: D000804:Angiotensin II / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II
references: Neuroscience. 2003;122(1):21-36
references: 14596846
references: Hypertension. 1996 Nov;28(5):818-24
references: 8901829
references: Am J Physiol Cell Physiol. 2007 Jan;292(1):C82-97
references: 16870827
references: Nature. 2010 Jan 21;463(7279):374-8
references: 20090754
references: Physiol Rev. 1977 Apr;57(2):313-70
references: 191856
references: J Clin Invest. 1988 Sep;82(3):1007-16
references: 2843564
references: J Mol Med (Berl). 2012 May;90(5):495-508
references: 22527880
references: Physiology (Bethesda). 2008 Apr;23:84-94
references: 18400691
references: Nature. 2000 Feb 10;403(6770):614
references: 10688186
references: High Alt Med Biol. 2007 Winter;8(4):278-85
references: 18081503
references: Biochim Biophys Acta. 2013 Jan;1833(1):213-24
references: 22575682
references: J Pharmacol Exp Ther. 1994 Aug;270(2):566-71
references: 8071849
references: Science. 1971 Jun 11;172(3988):1138-9
references: 4324923
references: Kidney Int. 2009 Jan;75(2):197-204
references: 18818681
references: Circ Res. 2008 Feb 29;102(4):488-96
references: 18096818
references: Cell. 2008 Jul 11;134(1):112-23
references: 18614015
references: Nature. 1998 May 21;393(6682):221-2
references: 9607758
references: Lancet. 1999 Feb 13;353(9152):541-5
references: 10028982
references: Kidney Int. 1994 Dec;46(6):1583-7
references: 7700013
references: Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H577-83
references: 20622110
references: Am J Physiol. 1996 Sep;271(3 Pt 1):E439-50
references: 8843736
references: Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H905-6
references: 17526648
references: J Cell Mol Med. 2008 Aug;12(4):1229-37
references: 18782187
references: Cardiovasc Res. 2007 Nov 1;76(2):204-12
references: 17698051
references: Blood Press. 1998 Jan;7(1):61-3
references: 9551879
references: Nat Protoc. 2009;4(11):1582-90
references: 19816421
references: Clin Sci (Lond). 1981 Dec;61 Suppl 7:245s-247s
references: 7318329
references: Eur J Appl Physiol. 2002 Jan;86(3):240-4
references: 11990733
references: Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14849-54
references: 21852574
references: Mol Endocrinol. 2006 May;20(5):953-70
references: 16141358
references: Circ Res. 1999 Feb 19;84(3):337-44
references: 10024308
references: Clin Sci (Lond). 2012 Sep;123(5):273-84
references: 22590974
references: J Mol Cell Cardiol. 2002 Dec;34(12):1561-8
references: 12505054
references: Am J Physiol. 1992 Apr;262(4 Pt 1):G645-50
references: 1348904
references: Biochim Biophys Acta. 2011 Mar;1808(3):1012-20
references: 20637721
references: Pflugers Arch. 2012 Jul;464(1):43-50
references: 22395411
references: Pharmacol Rev. 2000 Sep;52(3):415-72
references: 10977869
references: Aliment Pharmacol Ther. 2011 Oct;34(8):840-52
references: 21851372
references: Cell Death Differ. 2007 Jul;14(7):1267-74
references: 17431419
references: Curr Hypertens Rep. 2008 Apr;10(2):112-8
references: 18474177
references: Am J Physiol Renal Physiol. 2011 May;300(5):F1076-88
references: 21307128
references: Physiol Rev. 2004 Apr;84(2):489-539
references: 15044681
references: Int J Biochem Cell Biol. 2009 Oct;41(10):1805-16
references: 19703651
references: Regul Pept. 1993 Mar 19;44(2):207-13
references: 8385791
references: Life Sci. 1988;43(21):1747-54
references: 3193858
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D1160-7
references: 22121219