Mitochondria Biogenesis in health and disease
Our main interest is the biogenesis of mitochondria and their relevance in health and disease. About 30 % of the human proteome are proteins targeted to a site of action distant to their synthesis, highlighting the importance of correct intracellular targeting for cell function. Mitochondria are crucial for energy metabolism and physiology and they are involved in several medical conditions (neurodegeneration, cancer), ageing and apoptosis. Their biogenesis relies on specific protein import pathways since more than 98% of mitochondrial proteins are targeted from the cytosol.
We focus on proteins of the mitochondrial intermembrane space that are involved in respiration, metal homeostasis and apoptosis. Several of these proteins undergo oxidative folding by adopting intramolecular disulfide bridges. Our group has proposed the concept of an oxidative folding machinery existing in mitochondria, expanding thus the prevailing dogma that such a process only exists in the endoplamisc reticulum in eukaryotic cells. We study this machinery, its molecular mechanism and structural basis and its relevance for cell physiology. We combine molecular/cell biology approaches (mutagenesis, yeast genetics, confocal microscopy, cell fractionation), biochemical characterisation (protein purification, chemical crosslinking, redox assays, reconstitution and import assays), proteomics approaches (bottom-up and top-down) and biophysical analyses (light scattering, fluorescence, circular dichroism, calorimetry, surface plasmon resonance). Our ongoing efforts build on our contributions to key concepts, components, targeting signals and mechanistic features and develop to determine the relevance of the mitochondrial oxidative folding for redox homeostasis, signalling and the cell physiology.
Banci L, Bertini I, Cefaro C, Ciofi-Baffoni S, Gajda K, Felli IC, Gallo A, Pavelkova A, Kallergi E, Andreadaki M, Katrakili N, Pozidis C, Tokatlidis K. (2013) An intrinsically disordered domain has a dual function coupled to compartment-dependent redox control. J Mol Biol.,425(3): 594-608.
Chatzi A, Tokatlidis K. (2012) The Mitochondrial Intermembrane Space: A Hub for Oxidative Folding Linked to Protein Biogenesis. Antioxid Redox Signal. PMID 22901034
Banci L., Bertini I., Calderone, V., Cefaro C., Ciofi-Baffoni S., Gallo A., Kallergi, E., Lionaki, E., Pozidis, C. Tokatlidis K. (2011) Molecular recognition and substrate mimicry drive the electron transfer process between MIA40 and ALR. Proc Natl Acad. Sci USA 108: 4811-4816.
Banci L., Bertini I., Cefaro C., Cenacchi, L., Ciofi-Baffoni S., Felli, I.C., Gallo A., Gonnelli, L., Luchinat, E., Sideris D.P. Tokatlidis K. (2010) A molecular chaperone function of Mia40 triggers consecutive induced folding steps of the substrate in mitochondrial protein import. Proc Natl Acad. Sci USA 107: 20190-20195.
Banci L., Bertini I., Cefaro C., Ciofi-Baffoni S., Gallo A., Martinelli M., Sideris DP, Katrakili N. Tokatlidis K. (2009) MIA40 is an oxidoreductase catalyzing oxidative protein folding in mitochondria. Nature Structural and Molecular Biology 16: 198-206.
Sideris, D.P., Petrakis, N., Katrakili, N., Mikropoulou, D., Gallo, A., Ciofi-Baffoni, S., Banci, L., Bertini, I., Tokatlidis, K. (2009) A novel targeting signal primes precursors for correct cysteine docking onto Mia40 in the mitochondrial intermembrane space. J. Cell Biol. 187: 1007-1022.
Tokatlidis, K. (2005) A disulfide relay system in mitochondria Cell, 121, 965-967.
Lionaki E., Aivaliotis M., Pozidis C. and Tokatlidis K. (2010) The N-terminal shuttle domain of Erv1 determines the affinity for Mia40 and mediates electron transfer to the catalytic Erv1 core in yeast mitochondria Antiox. Redox Signal. 13(9):1327-1339
Tokatlidis, K., Junne, T., Moes, S., Schatz, G., Glick, B.S. Kronidou, N. (1996) Translocation arrest of an intramitochondrial sorting signal next to Tim11p, a novel protein of the inner membrane import site. Nature 384: 585-588.