Mitochondrial dysfunction is often an underlying cause of myocardial disease. In particular, many cardiac pathologies are associated with rapid and dramatic increases in mitochondrial permeability. These changes in permeability instigate a molecular chain of events that leads cardiomyocyte death. Our long-range goal 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, 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 component of the MPT pore has still not been defined. We have identified the mitochondrial phosphate carrier (PiC) as a novel CypD-interacting protein, and have generated strong preliminary data that the PiC is a positive regulator of MPT and cell death. Consequently, our central hypothesis is that PiC is an essential component of the MPT pore, and, therefore, a critical mediator of cardiomyocyte death. The objective of the present application, therefore, is to utilize genetic gain- and loss-of-function approaches to systematically evaluate the role of the PiC in MPT, cardiac cell death, and the progression of myocardial disease.
Our specific aims are as follows:
Specific Aim 1 : Define the physical and functional interaction between PiC and CypD;
Specific Aim 2 : Examine whether PiC upregulation induces MPT and cardiac pathology;
and Specific Aim 3 : Determine the functional requirement for PiC in MPT and cardiac cell death. The rationale for the proposed research 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.

Public Health Relevance

The death of heart cells is an underlying cause of human heart disease. The proposed research is aimed at uncovering the molecular mechanisms that lead to heart cell death. Once the key proteins that mediate cell death are identified, they can then be targeted as a means of treating patients with heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094404-05
Application #
8402844
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2008-12-16
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$340,589
Indirect Cost
$104,969
Name
University of Missouri-Columbia
Department
None
Type
Organized Research Units
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Gutiérrez-Aguilar, Manuel; Baines, Christopher P (2015) Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore. Biochim Biophys Acta 1850:2041-7
Gutiérrez-Aguilar, Manuel; Douglas, Diana L; Gibson, Anne K et al. (2014) Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. J Mol Cell Cardiol 72:316-25
Douglas, Diana L; Baines, Christopher P (2014) PARP1-mediated necrosis is dependent on parallel JNK and Ca²?/calpain pathways. J Cell Sci 127:4134-45
Marshall, Kurt D; Edwards, Michelle A; Krenz, Maike et al. (2014) Proteomic mapping of proteins released during necrosis and apoptosis from cultured neonatal cardiac myocytes. Am J Physiol Cell Physiol 306:C639-47
Marshall, Kurt D; Baines, Christopher P (2014) Necroptosis: is there a role for mitochondria? Front Physiol 5:323
McCommis, Kyle S; Douglas, Diana L; Krenz, Maike et al. (2013) Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux. J Am Heart Assoc 2:e000355
Gutierrez-Aguilar, Manuel; Baines, Christopher P (2013) Physiological and pathological roles of mitochondrial SLC25 carriers. Biochem J 454:371-86
McGee, Allison M; Baines, Christopher P (2012) Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition. Biochem J 443:185-91
McGee, Allison M; Baines, Christopher P (2011) Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death. Biochem J 433:119-25
Baines, Christopher P (2011) How and when do myocytes die during ischemia and reperfusion: the late phase. J Cardiovasc Pharmacol Ther 16:239-43

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