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Resource for the Visualization of Biological Complexity (RVBC)

Mitochondria

Mitochondria generate the ATP used to power the cell's molecular machinery by chemiosmotic reactions that occur on and across the inner membrane. Electron tomography, first applied to mitochondria at the RVBC, has shown that the invaginations in the mitochondrial inner membrane, called cristae, are not random infoldings (as depicted in older textbooks) but pleomorphic internal micro-compartments connected to the periphery and to each other by narrow tubular junctions that, in turn, can restrict diffusion of metabolites and proteins (Mannella et al., 1994, 1997, 2001, 2006).

Ongoing electron tomographic studies at the RVBC are helping to define the topological transitions exhibited by the mitochondrial inner membrane, for example, in response to changes in metabolic state and to mutations associated with mitochondrial dysfunction. Inner membrane remodeling may facilitate cytochrome c release during apoptosis (Scorrano et al. 2002) and mitigate effects of oxidative stress (Deng et al., 1999; Mannella et al., 2007; Mannella, 2008). Tomographic studies of mitochondria in model systems bearing mutations in subunit 6 of ATP synthase and in OPA1 (the gene associated with human dominant optic atrophy) have implicated these proteins in maintenance of normal crista topology (Celotto et al., 2006, Kanazawa et al., 2008).

These results have led to formulation of the hypothesis (Mannella, 2006) that mitochondrial inner membrane topology is a regulated parameter of the cell, under the control of proteins and lipids that affect membrane curvature and dynamics (fusion and fission), and that certain mitochondrial disorders might be caused by aberrant membrane topology.

Changes in internal organization of mitochondria associated with cell death and disease...

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

Celotto, A.M., Frank, A.C., McGrath, S.W., Fergestad, T., Van Voorhies, W.A. Buttle, K.F., Mannella, C.A., Palladino, M.J. (2006) Mitochondrial encephalomyopathy in Drosophila. J. Neurosci. 6:810-820.

Deng,Y., Kohlwein, S.D., Mannella, C.A. (2002) Fasting induces cyanide-resistant respiration and oxidative stress in the amoeba Chaos carolinensis: Implications for the cubic structural transition in mitochondrial membranes. Protoplasma 219:160-167.

Kanazawa, T, Zappaterra, M.D., Hasegawa, A., Wright, A.P., Newman-Smith, E.D., Buttle, K.F., McDonald, K., Mannella, C.A., van der Bliek, A.M. (2008) The C. elegans Opa1 homologue EAT-3 is essential for resistance to free radicals. PLoS Genet. 4:e1000022.

Mannella, C.A., Marko, M., Penczek, P., Barnard, D., Frank, J. (1994) Internal compartmentation of rat-liver mitochondria: Tomographic study using the high-voltage transmission electron microscope. Microscopy Research Tech. 27:278-283.

Mannella, C.A., Marko, M., Buttle, K. (1997) Reconsidering mitochondrial structure: new views of an old organelle. Trends Biochem. Sci. 22:37-38.

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.

Mannella, C.A. (2006) Structure and dynamics of mitochondrial inner membrane cristae. Biochim. Biophys. Acta, 1763:542-548.

Mannella, C.A. (2008) Structural diversity of mitochondria: Functional Implications. Annals NY Acad Sci. 1147:171-179.

Mannella, C.A., Buttle, K.F., Walker, D.W., Benzer, S. (2007) Electron tomographic studies of mitochondrial cristae topology: "Swirl" mitochondria of Drosophila flight muscle. Microsc. Microanal. 13(suppl 2):4-5.

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. Devel. Cell 2:55-67.