Christopher P. Baines, Ph.D.Associate Professor, Department of Biomedical Sciences
Office Location: 323 DCRC
Office Phone: 573-884-8767
The mitochondrial permeability transition (MPT) pore, a large, non-specific channel thought to span both mitochondrial membranes, is known to mediate the lethal permeability changes that initiate mitochondrial-driven death. The MPT pore was originally proposed to consist of the voltage-dependent anion channel (VDAC) in the outer membrane, the adenine nucleotide translocase (ANT) in the inner membrane, plus a regulatory protein cyclophilin-D (CypD) in the matrix. However, recent studies in gene-targeted mice have seriously questioned the validity of this paradigm. While we, and others, have shown that mice lacking CypD are indeed resistant to MPT and MPT-mediated cell death, mice lacking either VDAC or ANT still exhibit a classical MPT phenomenon and respond normally to cytotoxic stimuli. Consequently, with the exception of CypD, the precise molecular componentry of the MPT pore has still not been defined.
In order to identify new putative elements of the MPT pore, we are currently conducting genomic and proteomic screens of CypD-containing complexes. We are then employing a combinatorial approach that ranges from molecular and biochemical methodologies, through cell culture techniques, to studies in genetically engineered mice to assess the role of each candidate in MPT, cardiomyocyte death, and the pathogenesis of cardiac disease. The hope is that once key mitochondrial proteins that participate in mitochondrial dysfunction are identified, they can be targeted as a means of treating a whole array of human cardiac diseases.
- B.Sc. Pharmacology, Department of Pharmacology, University of Bath, Great Britain.
- Ph.D. Basic Medical Sciences, Department of Physiology, University of South Alabama.
- Postdoctoral training at the University of Rochester, University of Louisville, and Cincinnati Children's Hospital Medical Center.
- Research Faculty, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center.
- Fellow of the American Heart Association.
- Research funded by the National Institutes of Health and the American Heart Association.
Marshall KD, Edwards MA, Krenz M, Davis JW, Baines CP. Proteomic mapping of the proteins released during necrosis and apoptosis from cultured neonatal cardiac myocytes: comparison with apoptosis. Am J Physiol Cell Physiol. 2014; In Press.
Brown DA, Hale SL, Baines CP, del Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Moukdar F, Raza Shaikh S, Fisher-Wellman KH, Neufer PD Kloner RA. Reduction of early reperfusion injury with the mitochondria-targeting peptide Bendavia. J Cardiovasc Pharmacol Ther. 2014; 19:121-32.
Hiemstra JA, Liu S, Ahlman MA, Schuleri KH, Lardo AC, Baines CP, Dellsperger KC, Bluemke DA, Emter CA. A new twist on an old idea: a 2-dimensional strain assessment of cyclosporine as a therapeutic alternative for heart failure with preserved ejection fraction. Physiol Rep. 2013; 1:e00174. doi:10.1002/phy2.174.
McCommis KS, Douglas DL, Krenz M, Baines CP. Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux. J Am Heart Assoc. 2013; 2:e000355.
Gutierrez-Aguilar M, Baines CP. Physiological and Pathological Roles of Mitochondrial SLC25 Carriers. Biochem J. 2013; 454:371-86
Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012; 298:229-317.
McGee AM, Baines CP. Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition. Biochem J. 2012; 443:185-91.
McCommis KS, Baines CP. The role of VDAC in cell death: Friend or foe? Biochim Biophys Acta. 2012; 1818:1444-50.
McGee AM, Douglas DL, Liang Y, Hyder S, Baines CP. Elevated C1qbp expression protects breast cancer cells against cell death and promotes their migration and proliferation. Cell Cycle. 2011; 10:4119-27.
Schwartz Longacre L, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E, Downey JM, Gibbons RJ, Gottlieb RA, Heusch G, Jennings RB, Lefer DJ, Mentzer RM, Murphy E, Ovize M, Ping P, Przyklenk P, Sack MN, Vander Heide RS, Vinten-Johansen J, Yellon DM. New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute workshop. Circulation. 2011; 124;1172-9.
McCommis KS, McGee AM, Laughlin MH, Bowles DK, Baines CP. Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: beneficial effects of chronic exercise. Am J Physiol. 2011; 301:R1250-8
Baines CP., How and when do myocytes die during ischemia and reperfusion: the late phase., J Cardiovasc Pharmacol Ther. 2011 Sep;16(3-4):239-43.PMID: 21821522
Baines CP., The mitochondrial permeability transition pore and the cardiac necrotic program., Pediatr Cardiol. 2011 Mar;32(3):258-62. Epub 2011 Jan 6., PMID: 21210090
McGee AM, Baines CP., Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death., Biochem J. 2010 Dec 15;433(1):119-25.PMID:20950273
Emter CA, Baines CP., Low-intensity aerobic interval training attenuates pathological left ventricular remodeling and mitochondrial dysfunction in aortic-banded miniature swine., Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1348-56. Epub 2010 Sep 3.PMID: 20817828
Baines CP., The cardiac mitochondrion: nexus of stress., Annu Rev Physiol. 2010 Mar 17;72:61-80. Review. PMID:20148667
Baines CP., Role of the mitochondrion in programmed necrosis., Front Physiol. 2010 Nov 29;1:156.PMID: 21423395
Baines CP, Molkentin JD. Adenine nucleotide translocase-1 induces cardiomyocyte death through upregulation of the pro-apoptotic protein Bax. J Mol Cell Cardiol. 2009; 46:969-77.
Baines CP. The molecular composition of the mitochondrial permeability transition pore. J Mol Cell Cardiol. 2009.46:850-7.
Millay DP, Sargent MA, Osinska H, Baines CP, Barton ER, Vuagniaux G, Sweeney HL, Robbins J, Molkentin JD. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat Med. 2008;14:442-7.
Nakayama N, Chen X, Baines CP, Klevitsky R, Zhang H, Jaleel N, Chua BHL, Zhang X, Hewett TE, Robbins J, Houser SR, Molkentin JD. Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Invest. 2007; 117:2431-2434.
Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD. VDACs are dispensable for mitochondrial permeability transition and mitochondrial-dependent cell death. Nat Cell Biol. 2007; 9:550-555.
Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005; 434:658-662.
Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P. Protein kinase Cε interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003; 92:873-880.
Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P. Mitochondrial PKCε and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCε-MAPK interactions and differential MAPK activation in PKCε-induced cardioprotection. Circ Res. 2002; 90:390-397.