title: An analysis of the effects of Mn2+ on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays.
abstract: Manganese (Mn) toxicity is partially mediated by reduced ATP production. We have used oxidation rate assays--a measure of ATP production--under rapid phosphorylation conditions to explore sites of Mn(2+) inhibition of ATP production in isolated liver, brain, and heart mitochondria. This approach has several advantages. First, the target tissue for Mn toxicity in the basal ganglia is energetically active and should be studied under rapid phosphorylation conditions. Second, Mn may inhibit metabolic steps which do not affect ATP production rate. This approach allows identification of inhibitions that decrease this rate. Third, mitochondria from different tissues contain different amounts of the components of the metabolic pathways potentially resulting in different patterns of ATP inhibition. Our results indicate that Mn(2+) inhibits ATP production with very different patterns in liver, brain, and heart mitochondria. The primary Mn(2+) inhibition site in liver and heart mitochondria, but not in brain mitochondria, is the F₁F₀ ATP synthase. In mitochondria fueled by either succinate or glutamate+malate, ATP production is much more strongly inhibited in brain than in liver or heart mitochondria; moreover, Mn(2+) inhibits two independent sites in brain mitochondria. The primary site of Mn-induced inhibition of ATP production in brain mitochondria when succinate is substrate is either fumarase or complex II, while the likely site of the primary inhibition when glutamate plus malate are the substrates is either the glutamate/aspartate exchanger or aspartate aminotransferase.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. thomas_gunter@urmc.rochester.edu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Gunter
authors.forename: Brent
authors.initials: B
authors.lastname: Gerstner
authors.forename: Tobias
authors.initials: T
authors.lastname: Lester
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wojtovich
authors.forename: Jon
authors.initials: J
authors.lastname: Malecki
authors.forename: Steven G
authors.initials: SG
authors.lastname: Swarts
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
authors.forename: Claire E
authors.initials: CE
authors.lastname: Gavin
authors.forename: Karlene K
authors.initials: KK
authors.lastname: Gunter
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D008345:Manganese / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008345:Manganese; D000255:Adenosine Triphosphate
references.citation: J Biol Chem. 1955 May;214(1):489-95
references.pmid: 14367406
references.citation: EMBO J. 2001 Sep 17;20(18):5060-9
references.pmid: 11566871
references.citation: Eur J Pharmacol. 1995 Dec 7;293(4):377-83
references.pmid: 8748691
references.citation: Neurotoxicology. 1999 Apr-Jun;20(2-3):445-53
references.pmid: 10385903
references.citation: J Neurosci Res. 2007 Nov 15;85(15):3347-58
references.pmid: 17847118
references.citation: J Biol Chem. 1955 Nov;217(1):383-93
references.pmid: 13271402
references.citation: Exp Neurol. 1989 Dec;106(3):251-8
references.pmid: 2591523
references.citation: Neurotoxicology. 1999 Apr-Jun;20(2-3):433-44
references.pmid: 10385902
references.citation: J Biol Chem. 1984 Nov 10;259(21):13123-30
references.pmid: 6548475
references.citation: J Neurochem. 2004 Jan;88(2):266-80
references.pmid: 14690515
references.citation: J Mol Cell Cardiol. 2002 Oct;34(10):1259-71
references.pmid: 12392982
references.citation: Biochemistry. 1978 Jan 24;17(2):339-45
references.pmid: 413566
references.citation: Arch Biochem Biophys. 1986 Jul;248(1):305-23
references.pmid: 3015029
references.citation: Neuromolecular Med. 2009;11(4):281-96
references.pmid: 19757210
references.citation: Exp Neurol. 1993 Mar;120(1):89-94
references.pmid: 8477830
references.citation: Tokushima J Exp Med. 1975 Sep;22:5-10
references.pmid: 821178
references.citation: Rev Physiol Biochem Pharmacol. 1985;102:1-72
references.pmid: 2863864
references.citation: J Neurochem. 2008 Jun;105(5):1948-59
references.pmid: 18284614
references.citation: Am J Physiol. 1975 Oct;229(4):1080-4
references.pmid: 1190322
references.citation: J Neurosci Res. 2000 Jul 15;61(2):162-71
references.pmid: 10878589
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):473-7
references.pmid: 12515859
references.citation: J Biol Chem. 1977 Dec 10;252(23):8731-9
references.pmid: 925018
references.citation: Ann N Y Acad Sci. 1975 Dec 30;264:112-23
references.pmid: 4001
references.citation: Neurochem Res. 2004 Apr;29(4):709-17
references.pmid: 15098932
references.citation: J Pharmacol Exp Ther. 1988 Oct;247(1):156-61
references.pmid: 2902211
references.citation: Adv Enzymol Relat Subj Biochem. 1956;17:65-134
references.pmid: 13313307
references.citation: Neurotoxicology. 2009 Jul;30(4):727-9
references.pmid: 19465053
references.citation: Biochem J. 1989 Oct 15;263(2):453-62
references.pmid: 2597117
references.citation: Neurotoxicology. 2006 Sep;27(5):765-76
references.pmid: 16765446
references.citation: Neurotoxicology. 1984 Spring;5(1):13-35
references.pmid: 6538948
references.citation: Brain Res. 2006 Nov 6;1118(1):222-31
references.pmid: 16978592
references.citation: J Neurochem. 1996 Jan;66(1):386-93
references.pmid: 8522979
references.citation: Am J Physiol. 1993 Aug;265(2 Pt 2):H453-60
references.pmid: 8368348
references.citation: Neuromolecular Med. 2009;11(4):252-66
references.pmid: 19657747
references.citation: Ann N Y Acad Sci. 2004 Mar;1012:209-23
references.pmid: 15105268
references.citation: Biochem J. 1988 May 15;252(1):181-9
references.pmid: 3421900
references.citation: Am J Physiol. 1993 Aug;265(2 Pt 2):H445-52
references.pmid: 8368347
references.citation: Brain Res Bull. 2001 May 15;55(2):225-8
references.pmid: 11470319
references.citation: Dev Neurosci. 1994;16(5-6):291-300
references.pmid: 7768208
references.citation: Toxicol Appl Pharmacol. 2007 Jun 1;221(2):131-47
references.pmid: 17466353
references.citation: J Cereb Blood Flow Metab. 2003 Jun;23(6):756-71
references.pmid: 12796724
references.citation: Neurotoxicology. 2002 Jul;23(2):147-57
references.pmid: 12224755
references.citation: Biochem Soc Trans. 2005 Nov;33(Pt 5):897-904
references.pmid: 16246006
references.citation: J Biol Chem. 1986 Nov 15;261(32):15159-65
references.pmid: 3771569
references.citation: Neurotoxicology. 2008 Jul;29(4):569-76
references.pmid: 18565586
references.citation: J Biol Chem. 1989 Aug 15;264(23):13430-9
references.pmid: 2503501
references.citation: Biophys J. 1975 Apr;15(4):319-33
references.pmid: 236048
references.citation: Neurotoxicology. 2008 May;29(3):466-70
references.pmid: 18400301
references.citation: Eur J Biochem. 2002 Jul;269(13):3313-20
references.pmid: 12084073
references.citation: Biochemistry. 1976 Aug 24;15(17):3834-42
references.pmid: 8094
references.citation: Toxicol Appl Pharmacol. 1992 Jul;115(1):1-5
references.pmid: 1631887
references.citation: Biochem Pharmacol. 1985 Nov 1;34(21):3857-65
references.pmid: 4062960
references.citation: Brain Res. 1994 Sep 19;657(1-2):124-32
references.pmid: 7820609
references.citation: Neurology. 1993 Aug;43(8):1479-83
references.pmid: 8351000