Numerous cellular signaling pathways converge on mitochondria, orchestrating their fascinating intervention into fundamental, and radically diverse, cellular processes: aerobic metabolism, cell death via all recognized pathways (necrosis, apoptosis and autophagy) and hormone synthesis and secretion, to name a few. Our own work demonstrated that the close interactions of these organelles with the ER or the plasma membrane allow them to promptly respond with a large, transient increase of matrix [Ca2+] ([Ca2+]m), despite the low affinity of the ion transporters. Within the matrix, the activation of Ca2+‐sensitive dehydrogenases increases the availability of NADH, and thus electron flow through the respiratory chain, and ATP production. At the same time, Ca2+ sensitizes mitochondria to pathological challenges (oxidative stress, toxins), favoring pro-apoptotic morphological transitions and the release of caspase cofactors. Accordingly, we showed that oncogenes (e.g. Bcl-2) reduce mitochondrial Ca2+ loading, whereas tumor suppressors (e.g. Fhit) have the opposite effect. Rapid, Ca2+‐mediated signals, however, are only one of the regulatory mechanisms. In a longer time frame, the transcriptional programs, such as those controlled by the PPAR‐g coactivator 1 (PGC-1) family of transcription factors, coordinates the expression of a broad number of mitochondrial genes, including metabolic enzymes, respiratory complexes and uncoupling proteins. We showed that PGC-1 also modifies mitochondrial Ca2+signals, thus revealing a cross-talk between rapid relay mechanisms and long-term genomic programming. Finally, recent work revealed that ROS production, besides mitochondria-mediated cell death pathways, can also trigger differentiation programs, such as the trans-differentiation of muscle-derived stem cells into adipocytes. Based on this previous work, the main ongoing projects of the laboratory are the following: - Mitochondrial control of apoptosis and autophagy. We aim to characterize mitochondrial proteins and signals that control the processes of autophagy and apoptosis, and their relevance in muscle wasting. Focus will be placed on the regulatory proteins under the genomic control of PGC-1, and specifically on the VDAC isoforms. Work includes biochemical analyses (e.g. the identification of interactors and elucidation of macromolecular complexes), signaling studies and in vivo studies, upon expression of cDNA or RNAi in skeletal muscles - Regulation of mesenchimal stem cell differentiation. We aim to identify the muscle-derived (myokines) and fat-derived (adipokines) soluble factors, controlling the differentiation of stem cells and mitochondrial structure and function of differentiated cells. Work includes microarray analyses, signaling studies and bioenergetic assessment of cells. - Molecular determinants of oxidative damage. We investigate molecular mechanisms and cellular consequences of oxidative stress, and its role in aging and in the complex pathogenesis of mitochondrial diseases. Special focus is placed on p66shc, an important lifespan determinant associated to intramitochondrial ROS production - Oncogenes and tumor suppressors acting on mitochondrial signaling. We investigate the mitochondrial effects (second messenger generation, proteomic changes, bioenergetic alterations) triggered by signaling pathways active in cancer. Work includes microarray analysis of the expression of signaling proteins in databases of clinically characterized neoplastic samples.
Funded by:
Title: Mitochondrial calcium signalling in apoptosis and autophagy Agency: Associazione Italiana Ricerca sul Cancro (AIRC) Period: 2009 - 2011 Link: http://www.airc.it/
Title: A Mitochondrial Longevity Pathway: p66shc Mechanism Agency: National Insitute of Health (NIH) Period: 2007 – 2011 Link: http://www.nih.gov/
Title: Mitochondrial signals and proteins in age-related metabolic disorders Agency: Fondazione Cassa di Risparmio di Padova e Rovigo (CARIPARO) Period: 2009 – 2011 Link: http://www.fondazionecariparo.it/
Title: Understanding and combating age-related muscle weakness Agency: 7° Programma quadro (Comunità Europea) Period: 2009 - 2011 Link: http://cordis.europa.eu/fp7/home_it.html
Publications:
5 recent publications:
Rimessi, A., Marchi, S., Fotino, C., Romagnoli, A., Huebner, K., Croce, C.M., Pinton, P. and Rizzuto,R. Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis. Proc. Natl.Acad. Sci. USA (2009) 106, 12753−12758.
Chami, M., Oulès, B., Szabadkai, G., Tacine, R., Rizzuto, R., Paterlini−Bréchot, P. Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol Cell (2008) 5, 641−51.
Aguiari, P., Leo, S., Zavan, B., Vindigni, V., Rimessi, A., Bianchi, K., Franzin, C., Cortivo, R., Rossato, M., Vettor, R., Abatangelo, G., Pozzan, T., Pinton, P. and Rizzuto R. High glucose induces adipogenic differentiation of muscle−derived stem cells. Proc. Natl. Acad. Sci. USA (2008) 105,1226−1231.
Pinton, P., Rimessi, A., Marchi, S., Orsini, S., Migliaccio, E., Giorgio, M., Contursi, C., Minucci, S., Mantovani, F., Wieckowski, M.R., Del Sal, G., Pelicci, P.G. and Rizzuto, R. Protein Kinase Cb and Prolyl isomerase 1 regulate mitochondrial effects of the lifespan determinant p66Shc. Science (2007) 315, 659−663.
Szabadkai, G., Bianchi, K., Varnai, P., De Stefani, D., Wieckowski, M.R., Cavagna, D., Nagy, A.I., Balla, T. and Rizzuto, R. Chaperone mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J. Cell Biol. (2006) 175, 901−11
5 selected publications (all career):
Schon, E.A., Rizzuto, R., Moraes, C.T., Nakase, H., Zeviani, M. and Di Mauro, S. A direct repeat is a hotspot for large−scale deletion of human mitochondrial DNA. Science (1989) 244, 346−349
Rizzuto, R., Simpson, A.W.M., Brini, M. and Pozzan, T. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature (1992) 358, 325−328
Rizzuto, R., Brini, M., Murgia, M. and Pozzan, T. Microdomains of cytosolic Ca2+ concentration sensed by strategically located mitochondria. Science (1993) 262, 744−747.
Rizzuto, R., Pinton, P., Carrington, W., Fay, F.S.F., Fogarty, K.E., Lifshitz, L.M., Tuft, R.A. and Pozzan, T. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science (1998) 280, 1763−1766.
Brini, M., Pinton, P., King, M.P., Davidson, M., Schon, E.A. and Rizzuto, R. A calcium signaling defect in the pathogenesis of a mtDNA−inherited oxidative phosphorylation deficiency. Nature Medicine (1999) 5, 951−954.
Ultimo aggiornamento Martedì 07 Dicembre 2010 15:35
