Targeting mitochondria for resuscitation from cardiac arrest.
Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variable periods of time. However, reperfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as reperfusion injury. At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Studies in animal models of ventricular fibrillation have shown that limiting myocardial cytosolic Na+ overload attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation, which is the main bioenergetic function of mitochondria. This effect is associated with functional myocardial benefits such as preservation of myocardial compliance during chest compression and attenuation of myocardial dysfunction after return of spontaneous circulation. Additional studies in similar animal models of ventricular fibrillation have shown that mitochondrial injury leads to activation of the mitochondrial apoptotic pathway, characterized by the release of cytochrome c to the cytosol, reduction of caspase-9 levels, and activation of caspase-3 coincident with marked reduction in left ventricular function. Cytochrome c also "leaks" into the bloodstream attaining levels that are inversely proportional to survival. These data indicate that mitochondria play a key role during cardiac resuscitation by modulating energy metabolism and signaling apoptotic cascades and that targeting mitochondria could represent a promising strategy for cardiac resuscitation.
Ayoub
Iyad M
IM
Department of Medicine, Division of Critical Care Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
Radhakrishnan
Jeejabai
J
Gazmuri
Raúl J
RJ
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D016887:Cardiopulmonary Resuscitation; D045304:Cytochromes c / Q000378:metabolism; D006323:Heart Arrest / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D010085:Oxidative Phosphorylation; D012151:Resuscitation; D012964:Sodium / Q000378:metabolism
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D045304:Cytochromes c; D012964:Sodium; D002118:Calcium
FEBS Lett. 2003 Apr 24;541(1-3):1-5
12706809
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11357-62
9326614
Biochem J. 1995 Apr 1;307 ( Pt 1):93-8
7717999
J Mol Cell Cardiol. 1993 Dec;25(12):1461-9
7512654
Circ Res. 1999 Sep 3;85(5):403-14
10473670
J Mol Cell Cardiol. 2000 Jan;32(1):53-63
10652190
Cell Death Differ. 2000 Dec;7(12):1166-73
11175253
Blood. 2001 Sep 1;98(5):1542-8
11520805
J Biol Chem. 2004 Dec 17;279(51):53103-8
15475362
Biochem J. 1990 Feb 15;266(1):33-9
2106875
Cell. 2006 Jul 14;126(1):177-89
16839885
Crit Care Med. 2006 May;34(5):1580-2; author reply 1582
16633277
Circ Res. 2003 Feb 7;92(2):186-94
12574146
Arch Intern Med. 1992 Jan;152(1):145-9
1728910
Chest. 2005 Apr;127(4):1327-34
15821211
Curr Drug Targets Cardiovasc Haematol Disord. 2005 Aug;5(4):323-35
16101565
Cell Calcium. 2000 Nov-Dec;28(5-6):285-96
11115368
Ann Thorac Cardiovasc Surg. 2003 Feb;9(1):36-42
12667128
Crit Care Med. 2005 Nov;33(11):2599-605
16276186
Am J Physiol. 1996 Mar;270(3 Pt 2):H957-64
8780191
J Mol Cell Cardiol. 1991 Dec;23(12):1351-4
1811053
Circulation. 2008 Jan 29;117(4):e25-146
18086926
Circulation. 1999 Jun 8;99(22):2934-41
10359739
J Cell Biol. 1999 Mar 8;144(5):883-9
10085288
Circulation. 2001 Jul 10;104(2):234-9
11447092
Cell. 1997 Nov 14;91(4):479-89
9390557
Circ Res. 1999 Jun 25;84(12):1401-6
10381892
Crit Care Med. 2007 Oct;35(10):2329-36
17944021
Clin Chim Acta. 2004 Apr;342(1-2):127-36
15026273
Biochem J. 1999 Jul 15;341 ( Pt 2):233-49
10393078
Biochem J. 1987 Aug 1;245(3):915-8
3117053
N Engl J Med. 1992 Oct 8;327(15):1051-5
1522841
Int J Cancer. 2005 Aug 20;116(2):167-73
15800951
Am J Cardiol. 1980 Dec 1;46(6):967-75
7446428
Cell Death Differ. 1997 Jan;4(1):66-75
16465212
J Biol Chem. 1999 Apr 23;274(17):11549-56
10206961
Eur Heart J. 1997 Dec;18(12):1231-48
9508543
Biochem J. 1991 Sep 15;278 ( Pt 3):715-9
1654889
Pediatr Infect Dis J. 2005 May;24(5):467-70
15876954
Crit Care Med. 2002 Apr;30(4 Suppl):S166-71
11940795
Arch Dis Child. 2006 Jun;91(6):469-72
16443616
J Cell Sci. 2001 Aug;114(Pt 15):2855-62
11683418
Biochim Biophys Acta. 1998 Aug 10;1366(1-2):139-49
9714780
J Biol Chem. 2001 May 25;276(21):18361-74
11279112
Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1330-8
15790899
Resuscitation. 2003 May;57(2):131-7
12745180
J Surg Res. 1996 Feb 15;61(1):227-36
8769971
Pflugers Arch. 2003 Oct;447(1):8-13
12883892
Annu Rev Biochem. 1999;68:383-424
10872455
J Biol Chem. 1992 May 5;267(13):8834-9
1374381
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2398-409
11709405
JAMA. 1994 Mar 2;271(9):678-83
8309030
Annu Rev Physiol. 1986;48:389-402
3010819
Biochim Biophys Acta. 2006 Feb;1762(2):140-7
16054341
Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2904-11
15708960
J Cardiovasc Pharmacol. 2002 Apr;39(4):569-75
11904531
Appl Biochem Biotechnol. 2001 Feb;90(2):97-105
11297391
Science. 1998 Aug 28;281(5381):1309-12
9721092
Biochem Soc Symp. 1999;66:181-203
10989667
Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H767-75
17040974
J Appl Physiol (1985). 2007 Jul;103(1):55-65
17431086
Intensive Care Med. 2004 Nov;30(11):2126-8
15365608
Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2770-8
11356635
Circulation. 2003 Apr 8;107(13):1804-9
12665493
J Lab Clin Med. 2001 Jan;137(1):43-55
11150023
J Neurotrauma. 2001 Oct;18(10):1059-74
11686493
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1259-63
11818574
J Am Coll Cardiol. 2002 Dec 18;40(12):2110-6
12505221
Curr Opin Crit Care. 2003 Jun;9(3):199-204
12771670
JAMA. 1993 Sep 22-29;270(12):1433-6
8371442