Critical role of mitochondrial ROS is dependent on their site of production on the electron transport chain in ischemic heart.
Reactive oxygen species (ROS) generation has been implicated in many pathologies including ischemia/reperfusion (I/R) injury. This led to multiple studies on antioxidant therapies to treat cardiovascular diseases but paradoxically, results have so far been mixed as ROS production can be beneficial as a signaling mechanism and in cardiac protection via preconditioning interventions. We investigated whether the differential impact of increased ROS in injury as well as in protection could be explained by their site of production on the mitochondrial electron transport chain. Using amplex red to measure ROS production, we found that mitochondria isolated from hearts after I/R produced more ROS than non-ischemic when complex I substrate (glutamate/malate) was used. Interestingly, the substrates of complex II (succinate) and ubiquinone (sn-glycerol 3-phosphate, G3P) produced less ROS in mitochondria from I/R hearts compared to normal healthy hearts. The inhibitors of complex I (rotenone) and complex III (antimycin A) increased ROS production when glutamate/malate and G3P were used; in contrast, they reduced ROS production when the complex II substrate was used. Mitochondrial calcium retention capacity required to induce mitochondrial permeability transition pore (mPTP) opening was measured using calcium green fluorescence and was found to be higher when mitochondria were treated with G3P and succinate compared to glutamate/malate. Furthermore, Langendorff hearts treated with glutamate/malate exhibited reduced cardiac functional recovery and increased myocardial infarct size compared to hearts treated with G3P. Thus, ROS production by the stimulated respiratory chain complexes I and III has opposite roles: cardio-deleterious when produced in complex I and cardio-protective when produced in complex III. The mechanism of these ROS involves the inhibition of the mPTP opening, a key event in cell death following ischemia/reperfusion injury.
Department of Physiology, School of Medicine, University of Texas Health Science Center at San AntonioTX, USA; Department of Biomedical Engineering, University of Texas at San AntonioTX, USA.
Ngonidzashe B
NB
Madungwe
Sackler School of Medicine, Tel Aviv University Israel.
Netanel F
NF
Zilberstein
Department of Physiology, School of Medicine, University of Texas Health Science Center at San Antonio TX, USA.
Yansheng
Y
Feng
Department of Physiology, School of Medicine, University of Texas Health Science Center at San Antonio TX, USA.
Jean C
JC
Bopassa
Reactive oxygen species; electron transport chain; ischemia; mitochondrial permeability transition pore; reperfusion
Arch Biochem Biophys. 2009 Jan 1;481(1):30-6
18952046
Am J Cardiol. 2008 May 22;101(10A):14D-19D
18474268
Cardiovasc Res. 1999 Dec;44(3):470-3
10690277
Biochem Biophys Res Commun. 2002 Dec 6;299(3):465-71
12445824
Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R1159-68
17584954
Am J Physiol Heart Circ Physiol. 2010 Jan;298(1):H16-23
19880667
J Biol Chem. 1963 Jan;238:418-31
14020001
J Biol Chem. 2012 Aug 3;287(32):27255-64
22689576
J Heart Lung Transplant. 2007 Jun;26(6):604-9
17543784
FEBS Lett. 1974 May 15;42(1):68-72
4859511
Circ Res. 2015 Jan 30;116(3):531-49
25634975
J Biol Chem. 2009 Jul 17;284(29):19203-10
19478336
Biochim Biophys Acta. 2013 May;1827(5):578-87
23333272
Biochim Biophys Acta. 2009 Jun;1790(6):558-65
19364480
J Pharmacol Exp Ther. 2006 Dec;319(3):1405-12
16990510
Mol Cell Biochem. 1999 Jun;196 (1-2):59-67
10448903
Hypertension. 2003 Dec;42(6):1075-81
14581295
Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93
20421486
Biochem Pharmacol. 2009 Apr 15;77(8):1303-15
19071092
Can J Cardiol. 2013 Nov;29(11):1495-503
23770015
Genomics. 2000 Dec 1;70(2):190-200
11112347
Essays Biochem. 2010;47:53-67
20533900
Cell Mol Life Sci. 2006 Jun;63(12):1386-92
16715408
Nature. 2014 Nov 20;515(7527):431-5
25383517
Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78
16490224
Biochem J. 2004 Sep 1;382(Pt 2):511-7
15175007
J Neurochem. 2002 Mar;80(5):780-7
11948241
Circ Res. 2014 Jan 31;114(3):524-37
24481843
Science. 2008 Sep 12;321(5895):1493-5
18787169
Am J Cardiovasc Dis. 2012;2(3):223-36
22937492
Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2023-31
17237240
Brain Res Mol Brain Res. 1996 Feb;36(1):189-92
9011758
Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1900-8
15563525
Anesthesiology. 2011 Aug;115(2):242-53
21691195
Diabetes Obes Metab. 2010 Oct;12 Suppl 2:116-25
21029308
FEBS Lett. 2001 May 18;497(1):1-5
11376653
Arch Biochem Biophys. 1998 Feb 1;350(1):118-26
9466828
Circulation. 2013 Aug 20;128(8):873-934
23877260
Free Radic Biol Med. 2012 Jun 1-15;52(11-12):2201-8
22564526
J Biol Chem. 2004 Sep 17;279(38):39414-20
15262965
Biochim Biophys Acta. 2007 Aug;1767(8):1007-31
17631856
FEBS Lett. 1994 Feb 14;339(1-2):40-4
8313978
Annu Rev Pharmacol Toxicol. 2006;46:215-34
16402904
J Bioenerg Biomembr. 1994 Oct;26(5):509-17
7896766
Circ Res. 2013 Jan 18;112(2):e3-7
23329796
Basic Res Cardiol. 2006 Mar;101(2):180-9
16450075
Ross Fiziol Zh Im I M Sechenova. 2015 Apr;101(4):377-85
26336736
Mov Disord. 2010 Aug 15;25(11):1670-4
20568096
J Hepatol. 2011 Feb;54(2):348-56
21109325
J Bioenerg Biomembr. 1996 Apr;28(2):131-8
9132411
J Biol Chem. 2004 Nov 19;279(47):49064-73
15317809
Free Radic Biol Med. 2009 May 1;46(9):1283-97
19245829
J Biol Chem. 2003 Feb 21;278(8):5557-63
12482755
Ann Intern Med. 2005 Jan 4;142(1):37-46
15537682
Redox Biol. 2014 Jun 02;2:702-14
24944913
Biomed Res Int. 2015;2015:864946
26509170
Cardiovasc Res. 2009 Feb 15;81(3):449-56
18854381
PLoS One. 2015 Sep 10;10 (9):e0135988
26356837
J Mol Cell Cardiol. 2005 Feb;38(2):367-74
15698843
Am J Physiol Heart Circ Physiol. 2012 Apr 1;302(7):H1410-22
22268109
Cardiovasc Res. 2004 Apr 1;62(1):74-85
15023554
J Biol Chem. 2001 Oct 19;276(42):38388-93
11507097
J Biol Chem. 2002 Nov 22;277(47):44784-90
12237311
Am J Cardiovasc Dis. 2015 Aug 01;5(2):127-39
26309776
Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):29-38
15539615
N Engl J Med. 2014 Jul 10;371(2):177-8
25006725
Curr Pharm Des. 2007;13(8):845-63
17430185
Cell Res. 2011 May;21(5):817-34
21445095
Biochim Biophys Acta. 2014 May;1840(5):1596-604
24060746
Ann N Y Acad Sci. 2010 Jul;1201:96-103
20649545
J Biol Chem. 2008 Aug 1;283(31):21649-54
18522938
JAMA. 2007 Feb 28;297(8):842-57
17327526
Cardiovasc Res. 2006 Jan;69(1):178-85
16216231
Am J Physiol Cell Physiol. 2008 Feb;294(2):C460-6
18077608
Mitochondrion. 2007 Jun;7 Suppl:S154-67
17485243