title: A prototypical small-molecule modulator uncouples mitochondria in response to endogenous hydrogen peroxide production.
abstract: A high membrane potential across the mitochondrial inner membrane leads to the production of the reactive oxygen species (ROS) implicated in aging and age-related diseases. A prototypical drug for the correction of this type of mitochondrial dysfunction is presented. MitoDNP-SUM accumulates in mitochondria in response to the membrane potential due to its mitochondria-targeting alkyltriphenylphosphonium (TPP) cation and is uncaged by endogenous hydrogen peroxide to release the mitochondrial uncoupler, 2,4-dinitrophenol (DNP). DNP is known to reduce the high membrane potential responsible for the production of ROS. The approach potentially represents a general method for the delivery of drugs to the mitochondrial matrix through mitochondria targeting and H(2)O(2)-induced uncaging.
authors: WestChem School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK.
authors: Stephen J
authors: SJ
authors: McQuaker
authors: Casey L
authors: CL
authors: Quinlan
authors: Stuart T
authors: ST
authors: Caldwell
authors: Martin D
authors: MD
authors: Brand
authors: Richard C
authors: RC
authors: Hartley
mesh_terms: D019297:2,4-Dinitrophenol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009943:Organophosphorus Compounds; D011355:Prodrugs; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019297:2,4-Dinitrophenol
references: J Am Chem Soc. 2012 Jan 18;134(2):758-61
references: 22239373
references: Chembiochem. 2012 Feb 13;13(3):476-85
references: 22238158
references: Angew Chem Int Ed Engl. 2005 May 13;44(20):3133-5
references: 15828043
references: Free Radic Biol Med. 2009 Nov 15;47(10):1401-7
references: 19686842
references: Exp Gerontol. 2010 Aug;45(7-8):466-72
references: 20064600
references: J Am Chem Soc. 2008 Jul 30;130(30):9638-9
references: 18605728
references: Free Radic Biol Med. 2010 Aug 15;49(4):606-11
references: 20493945
references: PLoS One. 2011;6(7):e21746
references: 21799747
references: J Biol Chem. 2004 Sep 17;279(38):39414-20
references: 15262965
references: Trends Pharmacol Sci. 2012 Jun;33(6):341-52
references: 22521106
references: Tetrahedron. 2010 Mar 27;66(13):2384-2389
references: 20418941
references: Biochim Biophys Acta. 1998 Feb 25;1363(2):100-24
references: 9507078
references: Lancet. 2009 Oct 3;374(9696):1196-208
references: 19801098
references: J Am Chem Soc. 2008 Apr 9;130(14):4596-7
references: 18336027
references: Cell Signal. 2012 May;24(5):981-90
references: 22286106
references: J Am Geriatr Soc. 1972 Apr;20(4):145-7
references: 5016631
references: J Am Chem Soc. 2012 Aug 15;134(32):13510-23
references: 22816866
references: Antioxid Redox Signal. 2011 Oct 15;15(8):2197-208
references: 20919938
references: Biochem J. 2004 Sep 1;382(Pt 2):511-7
references: 15175007
references: J Biol Chem. 2012 Aug 3;287(32):27255-64
references: 22689576
references: Chem Commun (Camb). 2003 Nov 7;(21):2728-9
references: 14649832
references: Free Radic Biol Med. 2003 Oct 15;35(8):938-48
references: 14556858
references: Biochem J. 2009 Jan 1;417(1):1-13
references: 19061483
references: Antioxid Redox Signal. 2011 Dec 15;15(12):3021-38
references: 21395490
references: Methods Mol Biol. 2012;810:165-82
references: 22057567
references: J Biol Chem. 1948 Apr;173(2):807
references: 18910739
references: J Biol Chem. 2011 Sep 9;286(36):31361-72
references: 21708945
references: J Am Chem Soc. 2011 Mar 16;133(10):3260-3
references: 21322645
references: J Org Chem. 1998 Feb 6;63(3):889-894
references: 11672090
references: J Neurochem. 2001 Oct;79(2):266-77
references: 11677254
references: Cell Metab. 2011 Mar 2;13(3):340-50
references: 21356523
references: Nat Protoc. 2012 Apr 19;7(5):946-58
references: 22517261
references: Trends Biochem Sci. 2010 May;35(5):298-307
references: 20006514
references: Biosci Rep. 2006 Jun;26(3):231-43
references: 16850251