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Research Interests

My laboratory is engaged in studies of the mitochondrion, the organelle that generates most of the ATP that powers the cell's molecular machinery. Mitochondrial malfunctions can arise from errors in its own small genome or in the 1000 or more nuclear genes that encode for mitochondrial proteins and affect its membrane lipid composition. Numerous metabolic, neurological and muscular disorders result from mitochondrial dysfunction, and damage to mitochondria is strongly implicated in neurodegenerative disorders, such as Parkinson’s Disease.

This laboratory is particularly interested in factors that control the diffusion of ions, metabolites and proteins into and within this organelle. The first barrier to entry into the mitochondrion is its outer membrane, which contains thousands of copies of a pore-forming protein called VDAC (voltage-dependent, anion selective channel). Using cryo-electron microscopy, we have determined the structure of this important channel protein to a resolution of about 20 angstroms in two-dimensional crystals in the grown by phospholipase treatment of isolated mitochondrial outer membranes. Ongoing research, in collaboration with K. Kinnally (NYU), is aimed at visualizing structural changes in the outer membrane associated with onset of a new channel activity during programmed cell death (apoptosis).

The inner mitochondrial membrane contains the energy transducing macromolecular complexes of the respiratory chain. Although it is a continuous structure, the inner membrane invaginates to form micro-compartments called cristae. We have found, using electron tomography, that the cristae are connected to each other and to the peripheral region of the inner membrane by narrow tubular regions of varying length. Computer modeling and experiments indicate that the shape of the inner membrane influences such mitochondrial functions as efficiency of ATP production and release of soluble proteins (e.g. during apoptosis) by its effects on internal diffusion. We have proposed that the topology of the mitochondrial inner membrane is a regulated property of mitochondria, under the control of proteins and lipids that affect inner membrane curvature and fusion. Studies are underway to identify the factors that regulate inner membrane topology and changes associated with disease and aging.

Contact Information

E-mail: carmen@wadsworth.org

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