Dalton Cardiovascular Research Center

University of Missouri

Christopher P. Baines, Ph.D.

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

Selected Publications