Investigators and Program Directors

Research Interests

We are engaged in development of novel techniques for 3D electron microscopy and their application to study the cell's internal architecture. Special focus is on the mitochondrion, the organelle that, in differentiated cells and tissues, generates 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

We are 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 channel protein to a resolution of about 20 angstroms from two-dimensional crystals occurring in the mitochondrial outer membrane.  Knowing the structure of the native membrane form of VDAC has helped validate atomic structures of VDAC recently determined by NMR and x-ray crystallography of the recombinant protein in detergent micelles and lipid bicelles (Hiller et al., 2010).

The inner mitochondrial membrane contains the energy transducing macromolecular complexes of the respiratory chain. Using electron tomography, we have determined that the invaginations of the inner membrane called cristae are connected to each other and to the peripheral region of the inner membrane by narrow tubular regions of varying length and that inner membrane topology is dynamic, changing in response to cell signals and stresses. This has led to the hypothesis that the topology of the mitochondrial inner membrane is a parameter regulated by the cell to optimize mitochondrial function by controlling internal diffusion (Mannella, 2006a,b; 2008). We have also used electron tomography to discover and characterize protein tethers between mitochondria and the endoplasmic reticulum that functionally couple these membrane compartments (Csordas et al, 2006). Studies are now underway in several labs to identify the factors that regulate inner-membrane topology and mitochondrial-ER tethers, and changes associated with disease.

Contact Information

E-mail: carmen@wadsworth.org