Resource for the Visualization of Biological Complexity (RVBC)
The Mitochondrion
The insights from electron tomography are re-writing the textbooks on mitochondrial structure (Frey and Mannella, 2000). The internal compartments called cristae, formed by invagination of the mitochondrial inner membrane, were previously thought to be shelf-like with wide, slit-like openings into the peripheral region of the membrane. Tomographic analyses of a wide variety of mitochondria, isolated and in situ, have shown instead that cristae are connected to the peripheral membrane, and to each other, by narrow tubular segments. This design feature has important functional implications. Computer simulations, in collaboration with the "Virtual Cell" resource at the UConn Health Science Center, indicate that narrow tubular openings can restrict diffusion between intracristal and intermembrane spaces, leading to ADP depletion and local decrease in ATP production inside the cristae (Mannella et al., 2001). Another study, in collaboration with the Korsmeyer lab at Harvard, indicates that cytochrome c release from mitochondria during apoptosis is affected by cristae morphology. The pro-apoptotic protein, tBID, induces a remodeling of the inner membrane that widens the cristae openings and is associated with more complete release of cytochrome c (Scorrano et al., 2002). Other ongoing collaborative projects include studies of the regulation of mitochondrial inner membrane topology by dynamin-like proteins (Van der Bliek, UCLA), the structure of the relict mitochondrion in Cryptosporidium parvum (Keithley, Wadsworth Center), the physical association of mitochondria and ER associated with calcium signaling (Hajnozcky, Thomas Jefferson Univ), and structural alterations in the mitochondrial outer membrane associated with induction of a large channel (MAC) involved in apoptotic cytochrome c release (Kinnally, NYU).
Changes in internal organization of mitochondria associated with cell death and disease: (A) Normal, isolated liver mitochondrion (Mannella et al., 2001), (B) Liver mitochondrion treated with a protein (tBID) that induces programmed cell death or apoptosis (Scorrano et al., 2002), and (C) Mitochondrion from a patient with a mitochondrial myopathy (M. Huizing, 1998, PhD Thesis, Univ. Nijmegen).
References
Frey, T. G. and Mannella, C. A. (2000). The internal structure of mitochondria. Trends Biochem. Sc. 25:319-324.
Mannella, C. A., Pfeiffer, D. R., Bradshaw, P. C., Moraru, I., Slepchenko, B., Loew, L. M., Hsieh, C., Buttle, K., and Marko, M. (2001). Topology of the mitochondrial inner membrane: dynamics and bioenergetic implications. IUBMB Life 52:93-100.
Scorrano, L., Ashiya, M., Buttle, K., Oakes, S. A., Mannella, C. A., and Korsmeyer, S. J. (2002). A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Deve. Cell 2:55-67.