Mitochondrial Permeability and Heart Failure
Mitochondria are central in both energy production and cellular death pathways, yet a variety of questions concerning structure function relationships of mitochondria remain poorly understood.
The mitochondrial outer membrane (MOM) is more than a passive barrier separating the cytosol from the inner membrane. It is the site for integrating metabolic and cell signaling events, and provides a means for compartmentalizing discrete metabolic states VDACs are a small family of highly abundant channel proteins in the mitochondrial outer membrane that integrate both the bioenergetics of the cell and cell survival through their participation in apoptosis.
Two aspects are relevant to this proposal: VDAC2 directly interacts with the multi-domain pro-apoptotic protein Bak and considerable evidence suggests that VDACs are a component of the mitochondrial permeability transition pore (MPTP), an incompletely characterized large conductance channel activated by calcium overload and other stimuli. We hypothesize that VDAC2 and the MPTP interact and play an important role in maintenance of cell function and cell death. We have preliminary evidence for this concept and are interested in pursuing this by examining the in vivo consequences of loss of function and over-expression of VDAC2 in mutant mice using the heart as a model organ.
Our specific aims are to use knockout and transgenic mice to determine the consequences of loss and over-expression of VDAC2 using an ischemia-reperfusion (I/R) injury model, since it is known that I/R involves both intrinsic and extrinsic apoptotic pathways. We will genetically test to what degree this is mediated by pro- and anti-apoptotic proteins and the MPTP by breeding the VDAC2 mutants to Bak or Bax deficient mice, Bcl-2 over-expressing mice and mice lacking other components of the permeability transition pore, specifically cyclophilin D. Since mitochondrial dysfunction is a feature of stroke, heart failure, and numerous other processes these studies will delineate the mechanist role of MOM channel proteins in disease process.
Relevance of the project to IDDRC mission:
Mitochondrial function is central to the nervous system and this project is directed at understanding basic processes of apoptosis that is relevant to both developmental and homeostatic processes in the brain.
Mitochondrial disease is typically manifest as an encephalopathy, thus understanding VDAC in cell homeostasis and cell death has broad implications in disease mechanisms and recovery from injuries such as hypoxic-ischemic events.