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Terrence G. Frey

Professor Emeritus
Ph.D., University of California
Los Angeles
Department of Biology
Cell & Molecular Doctoral Program
Molecular Biology Masterís Program
Molecular Biology Institute
The Heart Institute

(619) 594-6756

Email - tfrey@mail.sdsu.edu

Structure of Biological Macromolecules and Macromolecular Assemblies; Membrane Structure and Function; Electron Microscopy and Image Processing

Our research interests are the structural study of biological assemblies by application of biophysical and biochemical methods. More specifically, we apply techniques of high resolution electron microscopy and digital image processing to study the structures of biological macromolecules, macromolecular assemblies, and whole organelles. Currently we are studying the structure and function of mitochondria using state of the art microscopic techniques, principally Electron Tomography. Electron Tomography is a technique which calculates the three-dimensional structure from a series of electron micrographs of cells or cellular components tilted over a range of angles. Our study of mitochondria has led, along with the work of several other research groups, to a new paradigm of mitochondrial structure in which the inner membrane of mitochondria is divided into two components. The inner boundary membrane is the component that lies along the outer membrane separated from it by approximately 3-7 nanometers. At numerous sites we find 30 nm diameter tubular extensions of the inner membrane projecting into the matrix toward the center of the mitochondrion forming cristae, the second component of the inner membrane. Numerous tubular cristae often merge forming large disklike cristae. These results have raised a number of questions about mitochondrial structure and function that we are currently addressing in collaboration with groups at SDSU and other research institution (See Frey and Mannella 2000 and MitoMovies)

(1) Is the mitochondrial inner membrane compartmentalized? Although the inner boundary membrane and the cristae membrane are one continuous surface, they are connected by discrete tubular crista junctions that are only 30nm in diameter. This suggests that the functions of the inner membrane may be compartmentalized by controlling the distribution of inner membrane proteins (See Frey et al. 2002).

(2) Do cristae grow from the addition of membrane proteins and lipids at tubular crista junctions? To answer this question we have studied the loss of crista in Neurospora mitochondria inhibition ofTom20, a critical component in protein import. Cristae membrane and crista junctions are lost at the same rate and precede loss of outer membrane and inner boundary membrane. (see Perkins et al. 2001).

(3) What are the changes in mitochondria structure during apoptosis? Mitochondria play a key role in initiating and/or regulating the apoptosis program with the release of cytochrome c and other proteins into the cytosol. We are using correlated confocal light microscopy and electron microscopy/tomography to study the structural changes in mitochondrial membrane conformation during apoptosis using different cell culture models. Our goal is to determine whether cytochrome c is released through specific pores in the outer membrane or by rupture of the outer membrane following swelling of the matrix. In this context we are also studying the possible role of the mitochondrial permeability transition and "remodeling" of the inner mitochondrial membrane in cytochrome c release

4) What effects do high concentrations of reactive oxygen species (ROS) have on the structure of mitochondria? Ischemia/reperfusion injury during a heart attack is believed to result an increase in reactive oxygen species that stimulates release of cytochrome c from mitochondria initiating apoptosis and/or necrosis. We are studying the effects of increasing ROS on cytochrome c release and changes in mitochondrial structure by correlated light and electron microscopy/tomography of mitochondria.

5) What are the physical chemical factors that control mitochondrial structure? In collaboration with colleagues in the Department of Math and Department of Physics we are refining the thermodynamic model developed by Renken et al. (2002) to explain the stability of mitochondrial membrane conformations observed by electron tomography.


Representative Publications

    Frey, T.G. and Perkins, G.A. (2006) “Electron Tomography of Intracellular Organelles” Ann. Rev. Biophys. Biomolec. Struct. (in press).

    A. Ponnuswamy, Nulton,J., Mahaffy, J.M., Salamon, P., Frey, T.G., and Baljon, A.R.C. (2005) “Modeling tubular shapes in the inner mitochondrial membrane” Physical Biology 2, 73-79.

    Frey, T.G., Renken, C.S., and Perkins, G.A. (2002) "Insight into mitochondrial structure and function from electron tomography." Biochim. Biophys. Acta 1555, 196-203.

    Renken, C.W., Siragusa, G., Perkins, G., Washington, L., Nulton, J., Salamon, P., and Frey, T.G. (2002) "A thermodynamic model describing the nature of the crista junction, a structural motif in the mitochondrion." J. Struct. Biol. 138, 137-144.

    Perkins, G.A., Renken, C.W., van der Kleij, I.J., Ellisman, M.H., Neupert, W., and Frey, T.G. "Electron tomography of mitochondria after the arrest of protein import aided by TOM19." Europ. J. Cell Biol. 80, 139-150 (2001).

    Frey, T.G. and Mannella, C.A. "The internal structure of mitochondria." Trends in Biochemical Sciences 25 319-324 (2000).

    Ph.D. students: Christian Renken

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