Unit of Cellular biochemistry
Lab of Cellular biochemistry
tel. ++39 051 209 1306
fax ++39 051 242576
Group Leader: Dott. Michela Rugolo
E-mail : michela.rugolo@unibo.it
Research in progress :
- Mitochondrial DNA haplogroup background in the 2,5 hexanedione toxicity of Leber’s hereditary optic neuropathy cells. The project aims at determining the influence of mtDNA haplogroup background in cell death following exposure to organic solvents. The main investigator of this research topic is Dr. Anna Ghelli.
- OPA1 isoforms and functions . OPA1 is a nuclear gene encoding for the mitochondrial dynamin-related GTPase OPA1, whose mutations cause autosomal dominant optic atrophy, the most common hereditary optic neuropathy. OPA1 has been shown to be required for mitochondrial fusion and cristae structural maintenance, thus influencing also the apoptotic pathway. The occurrence of eight isoforms in mammalians is likely to explain multiple OPA1 functions. The project aims at evaluating the role of different OPA1 mutations in the energetic efficiency of fibroblasts derived from patients. This project is driven by Dr. Claudia Zanna
- PTP and DOA mutations. Opening of the inner membrane permeability transition pore (PTP), a high-conductance channel, has been implicated in cell death. In this study we investigate whether the voltage threshold for PTP opening is influenced by OPA1 mutations casusing haplonisufficiency. Our aim is to assess whether PTP opening may represent the final common pathway through which reduced levels of OPA1 protein can presispose to cell death. This research project is driven by dr. Anna Maria Porcelli and Dr. Claudia Zanna.
- Mitochondrial DNA mutations and cancer predisposition. In addition to various neurodegenerative disorders, mitochondrial DNA mutations are associated also to some types of tumour. The aim of the project is the identification of the molecular signals, generated by mitochondria bearing mtDNA mutations, and directed to the nucleus to promote cell survival and tumour progression. We will take advantage of oncocytoma cell models recently developed in our laboratory and of a wide collection of tumor biopsies. Dr. Anna Maria Porcelli is is charge of this project.
- Characterization of cellular and biochemical properties of the pathogenic cyt b Y278C mutation in human cybrids. The aims include the establishment of mutant and control cybrid lines carrying this, and eventually other, pathogenic cyt b mutations; definition of the mitochondrial alterations in mutant cyt b / complex III cybrids, especially those associated with ATP and ROS production, under oxidative stress conditions. These studies will include comparison with bacterial models, to gain invaluable information for elucidating the molecular bases, and diagnosis of mitochondrial human myopaties with exercice intolerance, and related progressive and degenerative diseases.
- The goal of the proposed research is to appraise the biochemical effects of the Y278C mutation in cytochrome b, the only mtDNA-coded subunit of respiratory complex III, by using the unique cell model of cybrids, thus testing in human cells the mutation mechanism characterized at molecular level in bacterial model system. This project will be driven by Dr. Anna Ghelli
Funding :
- 2008 - Progetto di collaborazione Italia - Francia Galileo.
- Progetto AIRC Nazionale 2009-2011
- Telethon 2007-2009: Leber’s hereditary ptic neuropathy: systematic investigation on energy depletion and oxidative stress, and their relavance to cell death, using cybridP cell lines with 11778,3460, 14484 and 14459 mutant mitochondria.
Patents :
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Selected Publications :
- Porcelli AM, Ghelli A, Ceccarelli C, Lang M, Cenacchi G, Capristo M, Pennisi F, Morra I, Ciccarelli E, Melcarne A, Bartoletti-Stella A, Salfi N, Tallini G, Martinuzzi A, Carelli V, Attimonelli M, Rug 2010 The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization. Hum Molec Genet 19, 1019-1032
- Ghelli A, Porcelli AM, Zanna C, Vidoni S, Mattioli S, Barbieri A, Iommarini L, Pala M, Achilli A, Torroni A, Rugolo R, Carelli V 2009 The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber’s hereditary optic neuropathy cells to 2,5-hexanedione toxicity. Plos One 4, e7922
- Zanna C., Ghelli A., Porcelli AM., Karbowski M., Youle R.J., Schimpf S., Wissinger B., Cossarizza A., Pinti M., Vidoni S, Valentino ML, Rugolo M. and Carelli V. 2008 OPA1 mutations associated with dominant dptic dtrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 131, 352-367 (Neurosciences - IF 9,603)
- Gasparre G., Iommarini L., Porcelli A.M., Lang M., Ferri G.G., Ghelli A., Mariani E., Pennisi L.F., Kurelac I., Pasquinelli G., Bonora E., Ceccarelli C., Rugolo M., Salfi N., Romeo G. and Carelli V. (2008) A familial disruptive ND5 mutation in mitochondrial DNA is preferentially selected in oncocytic tumor cells. Human Mutation 30, 391-396 - IF 7.033
- Porcelli A.M., Ghelli A., Iommarini L., Mariani E., Hoque M., Zanna C., Gasparre G. and Rugolo M. (2008) The antioxidant function of Bcl-2 preserves cytoskeletal stability of cells with defective respiratory complex I. Cellular and Molecular Life Sciences 65, 2943-2951 - IF 4.655
- Amati-Bonneau P., Valentino ML, Reynier P , Gallardo E, Bornstein B, Boissière A, Campos I, Rivera H, González de la Aleja J, Carroccia R, Iommarini L, Labauge P, Figarella-Branger D, Marcorelles P, (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy “plus” phenotype. Brain 131: 338-351 - IF 7.217
- Ghelli A., Porcelli AM, Zanna C., Martinuzzi A, Carelli V. and Rugolo M. (2008) Protection against oxidant-induced apoptosis by exogenous glutathione in Leber’s hereditary optic neuropathy cybrids. Investigative Ophthalmology & Vision Science 49: 671-676 - IF 3.766
- Zanna C., Ghelli A., Porcelli AM., Karbowski M., Youle R.J., Schimpf S., Wissinger B., Cossarizza A., Pinti M., Vidoni S, Valentino ML, Rugolo M. and Carelli V. (2008) OPA1 mutations associated with dominant dptic dtrophy impair oxidative phosphorylation and mitochondrial fusion. Brain 131: 352-367 - IF 7.217
- Gasparre G., Porcelli A.M., Bonora E., Pennisi L.F., Iommarini L., Ghelli A., Moretti M., Toller M., Betts C., Carelli V., Martinelli G.N., Rinaldi Ceroni A., Curcio F., Rugolo M., Tallini G., Romeo G (2007) Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors. Proceedings National Academy Sciences USA 104: 9001-9006 - IF 9,643
- Bonora E., Porcelli A.M., Gasparre G., Biondi A., Ghelli A., Carelli V., Baracca A., Tallini G., Martinuzzi A., Lenaz G., Rugolo M. and Romeo G. (2006) Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Research 66: 6087-6069 - IF 7.656
- Porcelli AM, Ghelli A, Zanna C, Pinton P, Rizzuto Rand Rugolo M. (2005) pH difference across the outer mitochondrial membrane measured with a green fluorescent protein mutant. Biochem. Biophys. Res. Comm 326: 799-804 - IF 2.836
- Zanna C., Ghelli A., Porcelli A.M., Carelli V., Martinuzzi A. and Rugolo M. (2005) Caspase-independent death of Leber’s hereditary optic neuropathy cybrids is driven by energetic faileure and mediated by AIF and endonuclease G. Apoptosis 10: 997-1007 IF 3,421
- Porcelli AM, Ghelli, Zanna C, Valente P, Ferroni S and Rugolo M. (2004) Apoptosis induced by staurosporine in ECV304 cells requires cell shrinkage and up-regulation of Cl- conductance. Cell Death Differentiation 11: 655-662 - IF 7.463
- Ghelli A, Zanna C, Porcelli AM, Schapira AHV, Martinuzzi A, Carelli V and Rugolo M. (2003) Leber’s Hereditary Optic Neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium. Journal Biological Chemistry 278: 4145-4150 - IF 5.808
Postgraduate training :
Mitochondria in cell physiology and pathology
Collaborations :
Mitochondrial neuropaties - Valerio Carelli, Dip. di Scienze Neurologiche, Univ. di Bologna;
Modelling of cytochrome b mutations in bacteriaFevzi Daldal, University of Pennsylvania, Philadelphia, USA
Cybrid generation -Andrea Martinuzzi, Istituto E.Medea, Conegliano Veneto
OPA1 functions - Dr. Guy Lenaers, University of Montpellier, France
PTP and neurodegeneration -prof. Paolo Bernardi, Università di Padova.
Links :
Postgraduate training
http://www.dipartimentobiologia.it/doctoraltraining/rugolo.asp
Integrated Live Cell Imaging Lab
http://www.dipartimentobiologia.it/facilities/livecell.htm
Research group :
Anna Ghelli (Research Associate)
Anna Maria Porcelli Research Associate
Michela Rugolo (Associate professor)
Claudia Zanna (Post-doc)
Sara Vidoni (PhD student)
Mariantonietta Capristo (PhD student)
