Christopher P. Baines, Ph.D.

Email: bainesc@missouri.edu

Research Interests: role of mitochondria in cell death and molecular mechanisms of cardiovascular disease

Mitochondrial dysfunction is often an underlying cause of myocardial disease. In particular, cardiac pathologies such as ischemia/reperfusion injury, heart failure, diabetic cardiomyopathy, anti-cancer agent-induced cardiotoxicity, etc., are associated with rapid and dramatic increases in mitochondrial permeability. These changes in permeability lead to ATP depletion, excessive production of reactive oxygen species, and ultimately swelling and rupture of the organelle, thereby instigating a molecular chain of events that leads to cardiomyocyte death. The long-range goal of our lab is to understand how specific mechanisms of mitochondrial-driven death can be targeted for the prevention of myocardial disease.

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), the adenine nucleotide translocase (ANT), and cyclophilin-D (CypD). However, while we, and others, have shown that mice lacking CypD are 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, 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.

Selected Publications:
Baines CP. The Mitochondrial permeability transition pore as a target of cardioprotective signaling. Am J Physiol. 2007; 293:H903-H904.

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; 117:2431-2444.

Diwan A, Koesters AG, Odley AM, Pushkaran S, Baines CP, Spike BT, Daria D, Jegga AG, Geiger H, Aronow BJ, Molkentin JD, Macleod KF, Kalfa TA, Dorn GW 2nd. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci. 2007; 104:6794-6799.

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, Molkentin JD. Stress signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol. 2005; 38:47-62.

Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P. Protein kinase Ce 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 PKCe and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCe-MAPK interactions and differential MAPK activation in PKCe-induced cardioprotection. Circ Res. 2002; 90:390-397.