Dalton Cardiovascular Research Center

University of Missouri

Christopher P. Baines, Ph.D.

Associate Professor, Department of Biomedical Sciences, College of Veterinary Medicine
Office Location: 323 DCRC
Office Phone: 573-884-8767
BainesC@missouri.edu

Research Interests

Role of mitochondria in cell death; Molecular mechanisms of cardiovascular disease

Research Description

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 the 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) 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.

Professional Background

• 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.

Selected Publications

1. Marshall KD, Klutho PJ, Song L, Roy R, Krenz M, Baines CP. Cardiac myocyte specific expression of FASTKD1 prevents myocardial infarction-induced rupture. J Am Heart Assoc. 2023; 12:e025867.
2. Onyali V, Nourian Z, Boerman EM, Hanft LM, Krenz M, Baines CP, Duan D, McDonald KS, Domeier TL. Calcium handling and cardiac damage following acute ventricular preload challenge in the DMDmdx4Cv mouse heart. Am J Physiol. 2023; 325:H1168-H1177.
3. Queathem ED, Fitzgerald M, Welly RJ, Rowles C, Schaller K, Bukhary S, Baines CP, Rector RS, Padilla J, Manrique C, Lubahn DB, Vieira-Potter VJ. Suppression of estrogen receptor beta (ERβ) classical genomic activity enhances systemic and adipose-specific response to chronic beta-3 adrenergic receptor (β3AR) stimulation. Front. Physiol. 2022; 13:920675.
4. Zhao J, Liu X, Blayney A, Zhang Y, Gandy L, Mirsky PO, Smith N, Zhang F, Linhardt RJ, Chen J, Baines CP, Loh SN, Wang C. Intrinsically disordered N-terminal domain (NTD) of p53 interacts with mitochondrial PTP regulator cyclophilin-D. J Mol Biol. 2022; 434:167552.
5. Clart LM, Welly RJ, Queathem ED, Rector RS, Padilla J, Baines CP, Kanaley JA, Lubahn DB, Vieira-Potter VJ. Role of ER Genomic Signaling in Adipocyte Metabolic Response to Wheel Running Following Ovariectomy. J Endocrinol. 2021; 249:223-237.
6. Baines CP, Gutiérrez-Aguilar M. The mitochondrial permeability transition pore: Is it formed by the ATP synthase, adenine nucleotide translocators or both? Biochim Biophys Acta Bioenerg. 2020; 1861:148249.
7. Klutho PJ, Dashek RJ, Baines CP. Genetic Manipulation of SPG7 or NipSnap2 Does Not Affect Mitochondrial Permeability Transition. Cell Death Discov. 2020; 6:5.
8. Wang X, Zhang Z, Li H, Zhang L, Baines CP, Ding S. Subcellular NAMPT-mediated NAD+ salvage pathway and their role in bioenergetics and neuronal protection after ischemic injury. J Neurochem. 2019; 151:732-48.
9. Mishra PK, Adameová A, Hill JA, Baines CP, Kang PM, Downey J, Narula J, Takahashi M, Abbate A, Piristine HC, Kar S, Su S, Higa JK, Kawasaki NK, Matsui T. Guidelines for evaluating myocardial cell death. Am J Physiol. 2019; 317:H891-H922.
10. Marshall KD, Krenz M, Baines CP. The novel cyclophilin-D binding protein FASTKD1 protects cells against oxidative stress-induced death. Am J Physiol. 2019; 317:C584-99.
11. Jones JL, Peana D, Veteto AB, Lambert MD, Nourian Z, Karasseva NG, Hill MA, Lindman BR, Baines CP, Krenz M, Domeier TL. TRPV4 increases cardiomyocyte calcium cycling and contractility in the aged heart following hypoosmotic stress. Cardiovasc Res. 2019; 115:46-56.
12. Ruyle BC, Klutho PJ, Baines CP, Heesch CM, Hasser EM. Hypoxia activates a neuropeptidergic pathway from the paraventricular nucleus of the hypothalamus to the nucleus tractus solitarii. Am J Physiol Regul Integr Comp Physiol. 2018; 315:R1167-82.
13. Baines CP, Gutierrez-Aguilar M. The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore. Cell Calcium. 2018; 73:121-30.
14. Wang X, Nichols L, Grunz-Borgmann EA, Sun Z, Meininger GA, Domeier TL, Baines CP, Parrish AR. Fascin2 regulates cisplatin-induced apoptosis in NRK-52E cells. Toxicol Lett. 2017; 266:56-64.
15. Jang S, Lewis TS, Powers C, Khuchua Z, Baines CP, Wipf P, Javadov S. Elucidating mitochondrial electron transport chains supercomplexes in the heart during ischemia-reperfusion. Antiox Redox Signal. 2017; 27:57-69.
16. Hiemstra JA, Lee Di, Chakir K, Gutierrez-Aguilar M, Marshall KD, Zgoda PJ, Cruz-Rivera N, Dozier DG, Ferguson BS, Heublein DM, Burnett JC, Scherf C, Ivey JR, Minervini G, McDonald KS, Baines CP, Krenz M, Domeier TL, Emter CA. Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine. J Am Heart Assoc. 2016; 5:e003277.
17. Gutierrez-Aguilar M, Baines CP. Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta. 2015; 1850:2041-7.
18. Douglas DL, Baines CP. PARP1-mediated necrosis is dependent on parallel JNK and Ca2+/calpain pathways. J Cell Sci. 2014; 127:4134-45.
19. Hiemstra JA, Gutierrez-Aguilar M, Marshall KD, McCommis KS, Zgoda P, Cruz-Rivera N, Jenkins N, Krenz M, Domeier TL, Baines CP, Emter CA. A new twist on an old idea part 2: cyclosporine preserves normal mitochondrial but not cardiomyocyte function in mini-swine with compensated heart failure. Physiol Rep. 2014; 2:e12050. (Co-corresponding Author).
20. Kalogeris TJ, Baines CP, Korthuis RJ. Adenosine prevents TNF-induced decrease in endothelial mitochondrial mass through activation of eNOS-PGC1 regulatory axis. PLoS One. 2014; 9:e98459.
21. Gutierrez-Aguilar M, Douglas DL, Gibson AK, Domeier TL, Molkentin JD, Baines CP. Genetic manipulation of the mitochondrial phosphate carrier does not affect mitochondrial permeability transition in the heart. J Mol Cell Cardiol. 2014; 72:316-25.
22. Kwong JQ, Davis J, Baines CP, Sargent MA, Karch J, Wang X, Huang T, Molkentin JD. Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ. 2014; 21:1209-17.
23. 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; 306:C639-47.