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Investigators and Program Directors

Carmen A. Mannella

Carmen A. Mannella

Emeritus Research Scientist, Wadsworth Center, Cellular and Molecular Basis of Diseases
Professor, School of Public Health, Biomedical Sciences

Ph.D., University of Pennsylvania (1974)
Postdoctoral training, Roswell Park Memorial Institute and St. Louis University


Structure of a native liver mitochondrion. This three-dimensional model of a typical mitochondrion shows that the inner membrane invaginations called cristae form internal interconnected microcompartments. With collaborators worldwide, the Mannella group has shown that changes in this membrane’s topology can alter internal diffusion pathways and thereby affect mitochondria function. Studies are now underway in many laboratories to understand cellular regulation of inner membrane topology and changes associated with normal development and disease.

Research Interests

We are part of the 3D-EM Group, engaged in development and application of novel techniques for electron microscopy (EM). The focus of our lab is 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 that affect the organelle’s metabolism, dynamics, membrane lipid composition and biogenesis. 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.

A major goal is to understanding the factors that control 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 tools of biochemistry and biophysics (including cryo-EM), we determined the structure of this channel protein in its native membrane to a resolution of about 20 angstroms and proposed a mechanism for its reversible closure or gating (Mannella, 1997, 1998).  The structural data has been used to 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) and, in turn, the proposed gating mechanism recently has been validated by solid state NMR and other techniques (Zachariae et al., 2012, Structure 20:1540).

The inner mitochondrial membrane contains the energy transducing macromolecular complexes of the respiratory chain. We were the first to use EM tomography to show that the infoldings of the inner membrane (cristae) are micro-compartments, connected to each other and to the peripheral region of the inner membrane by narrow tubular regions of varying length (Mannella et al., 1994, 1997). Inner membrane topology can change dramatically in response to cell signals, stresses and disease-causing mutations, altering internal diffusion pathways. These observations have led to the hypothesis that inner membrane topology is a parameter regulated by the cell to optimize mitochondrial function (Mannella, 2006a,b; 2008). We have also used EM 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 (e.g., Raturi and Simmen, 2013, BBA 1833:213).

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