Mitochondria in Disease Pathogenesis and Therapy

• Paolo Bernardi (Professor)
  

• Emy Basso (Staff Scientist)
• Valeria Petronilli (CNR Scientist)
• Andrea Rasola (Assistant Professor)

• Alessia Angelin (Postdoctoral Fellow)
• Valentina Giorgio (Postdoctoral Fellow)
• Giulia Guzzo (PhD Student)
• Emma Jones (Undergraduate Student)
• Ionica Masgras (PhD Student)
• Boris Pantic (PhD Student)
• Marco Pustetto (Undergraduate Student)
• Marco Sciacovelli (PhD Student)
• Justina Šileikitė (PhD Student)
• Sophia von Stockum (PhD Student)
• Alessandra Zulian (Postdoctoral Fellow)

Scientific activity:

• Scientific Outline
• Funded by:
• Publications

Scientific Outline

Our laboratory is rooted in the tradition of mitochondrial Bioenergetics, with specific emphasis on regulated permeability changes mediated by the Ca²⁺-dependent permeability transition pore (PTP), their regulation by cellular signals, their role in cell physiology and pathology, and their exploitation as targets for pharmacological intervention in conditions where mitochondria contribute to disease pathogenesis. This long-haul program started in the early 1990s with the biophysical characterization of PTP regulation, the discovery of the pore voltage-dependence and modulation by the proton electrochemical gradient; and continued with the purification of Cyclophilin (CyP) D, the receptor for the PTP desensitizer cyclosporin (Cs) A, which in 2005 led to the generation of CyP-D null mice in collaboration with Mike Forte (Vollum Institute, Portland OR). In close collaboration with Fabio Di Lisa, the group has established and validated reliable methods to monitor mitochondrial function and PTP activity in situ, with studies that have substantially contributed to define the role of mitochondria in several paradigms of cell death. The next step was the development of relevant in vivo models of disease. In collaboration with Paolo Bonaldo (University of Padova), the major discovery was made that PTP opening is a causative event in collagen (col) VI muscular dystrophies, and that the mouse disease model can be cured with CsA, with non-immunosuppressive CsA derivatives acting on CyP-D, or by genetic ablation of CyP-D. These findings have been validated in cultured cells from patients with colVI diseases (Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy) and in an encouraging pilot trial with CsA. A second area of research is the study of mitochondrial bioenergetics in mitochondrial DNA diseases, with the aid of high resolution respiratory measurements with the Seahorse XF extracellular analyzer. A third area of research is the role of mitochondria in cancer, with specific emphasis on how mitochondria can be targeted to reactivate tumor-specific apoptosis. The laboratory has studied an experimental drug acting on the Bcl-2 oncogene, and is currently running a robust program coordinated by Andrea Rasola on the identification of mitochondrial oncogenes and PTP signalling pathways involved in cell survival.

Current programs:
1. Molecular definition of the PTP and its regulation by CyP-D;
2. Molecular definition of mitochondrial Ca²⁺ channels;
3. Development and validation of novel PTP inhibitors;
4. Non-immunosuppressive cyclosporins in the mitochondrial therapy of muscular dystrophies;
5. Bioenergetics of mitochondrial DNA diseases;
6. Mitochondrial signalling in tumor transformation;
7. Development of proapoptotic drugs acting on tumor mitochondria

Funded by:

	MIUR, Italy
	University of Padova
	Telethon, Italy
	AIRC, Italy
	NIH-PHS, USA
	Fondazione Cariparo
	AFM, France

Publications:

5 recent publications:

1. Angelin, A., Tiepolo, T., Sabatelli, P., Grumati, P., Bergamin, N., Golfieri, C., Mattioli, E., Gualandi, F., Ferlini, A., Merlini, L., Maraldi, N.M., Bonaldo, P. and Bernardi, P. (2007) Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins, Proc. Natl. Acad. Sci. U.S.A. 104, 991-996
   
2. Chiara, F., Castellaro, D., Marin, O., Petronilli, V., Brusilow, W.S., Juhaszova, M., Sollott, S.J., Forte, M., Bernardi, P. * and Rasola, A.* (2008) Detachment of type II hexokinase from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels, *Corresponding authors. PLoS One, 3, e1852
   
3. Basso, E., Petronilli, V., Forte, M.A. and Bernardi, P. (2008) Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation, J. Biol. Chem. 283, 26307-26311
4. Merlini, L., Angelin, A., Tiepolo, T., Braghetta, P., Sabatelli, P., Zamparelli, A., Ferlini, A., Maraldi, N.M., Bonaldo, P. and Bernardi, P. (2008) Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies, Proc. Natl. Acad. Sci. U.S.A. 105, 5225-5229
   
5. Rasola A, Sciacovelli M, Chiara F, Pantic B, Brusilow WS, Bernardi P (2010) Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition. Proc Natl Acad Sci USA 107:726-731

5 selected publications (all career):

1. Bernardi, P. and Azzone, G.F. (1981) Cytochrome c as an Electron Shuttle Between the Outer and Inner Mitochondrial Membranes. J. Biol. Chem. 256, 7187-7192
2. Bernardi, P. (1992) Modulation of the Mitochondrial Cyclosporin A-Sensitive Permeability Transition Pore by the Proton Electrochemical Gradient. Evidence that the Pore can be Opened by Membrane Depolarization. J. Biol. Chem. 267, 8834-8839
3. Nicolli, A., Basso, E., Petronilli, V., Wenger, R.M. and Bernardi, P. (1996) Interactions of Cyclophilin with the Mitochondrial Inner Membrane and Regulation of the Permeability Transition Pore, a Cyclosporin A-sensitive Channel. J. Biol. Chem. 271, 2185-2192
   
4. Bernardi, P. (1999) Mitochondrial Transport of Cations: Channels, Exchangers and Permeability Transition. Physiol. Rev. 79, 1127-1155
   
5. Irwin, W., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Volpin, D., Bressan, G.M., Bernardi, P.*, and Bonaldo, P.* (2003) Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency, *Corresponding authors. Nat. Genet. 35, 367-371