How is mitochondrial form-function relationship established?
What is its role in cell signalling and in age-associated diseases?
Mitochondria are crucial organelles in cell life and death: they synthetize most of cellular ATP, integrate signalling pathways and amplify cell death. This versatility is mirrored by their dynamic morphology, ultrastructure and juxtaposition to the endoplasmic reticulum, all controlled by a set of “mitochondria-shaping proteins”. We are interested in understanding the mitochondrial form-function relationship in health and disease. We use an integrated approach of genetics, advanced imaging, biochemistry, physiology and electron tomography to unravel the role of mitochondrial dynamics in signalling and in complex cellular responses.
Besides being crucial organelles in ATP synthesis, mitochondria control multiple signaling cascades, amplify cell death and participate in a plethora of diseases ranging from genetic conditions to the diseases of ageing that we study at VIMM. Mitochondrial function and dysfunction are mirrored by shape changes, controlled by a small set of mitochondria-shaping proteins that include Optic atrophy 1 (Opa1), Mitofusins (Mfn) 1&2, Dynamin related protein 1 (Drp1), Mitochondrial fission factor (Mff), Mitochondrial Dynamics (MiD)49&51, Fission 1 (Fis1).
The Scorrano lab has changed classical tenets in the field of apoptosis and mitochondrial pathophysiology and propelled the fields of mitochondrial dynamics and interorganellar contact sites. His lab discovered the Opa1-dependent “molecular staple” holding cristae junctions tight and exploited it in vivo to correct mitochondrial diseases and blunt muscular atrophy, stroke and heart ischemia; identified Mfn2, mutated in a peripheral neuropathy as the first molecular bridge between endoplasmic reticulum and mitochondria; understood how mitochondrial shape controls the outcome of autophagy; defined the molecular link between cristae shape, cellular respiration and growth; identified the essential role of mitochondrial fusion in heart development. We now wish to understand the molecular mechanisms and pathophysiological consequences of mitochondrial shape changes and contacts with the ER in health and in diseases associated to ageing.
What are the molecular mechanisms of mitochondrial structure regulation?
Using a multipronged proteomic and genetic approach we unveiled that Opa1 is epistatic to the MICOS multiprotein complex in cristae shape regulation in mammals (Glytsou et al, Cell Reports 2016). We are now exploiting our proteomic catalogue of inner mitochondrial membrane protein complexes modified during cristae remodeling to characterize the function of novel regulators of mitochondrial structure (Lukas Alan). Moreover, we are generating and characterizing conditional animal models of mitochondrial fission to investigate their function in cell biology and in heart and blood disease (Tiago Fonseca).
What is the role of Opa1-regulated mitochondrial ultrastructure in tissue damage?
Using a variety of genetic models, our lab demonstrated that the Opa1-controlled cristae remodeling pathway is an essential component of heart, brain, muscle dysfunction and thus placed Opa1 as a targetable component to counteract stroke, neurodegeneration, hearth ischemia-reperfusion and muscle mass loss (Cogliati et al., Cell 2013; Varanita et al., Cell Metab. 2015; Civiletto, Varanita et al., Cell Metab. 2015). We are now interested in understanding how we can epigenetically increase Opa1 levels to correct mitochondrial dysfunction in primary mitochondrial disorders as well as in acquired conditions such as muscle mass loss and heart damage (Camilla Bean). Furthermore, because of the crucial role of Opa1 in neurodegeneration (Costa et al., EMBO Mol Med 2010), we are investigating the relationship between mitochondria and neurodegeneration in the context of optic atrophies, a genetic model for the much more common conditions of glaucoma (Marta Zaninello, Keiko Iwata)
What is the role of mitochondrial shape and of autophagy in heart diseases?
Stemming from our discovery that mitochondrial shape is a determinant of autophagy (Gomes et al, Nat Cell Biol 2011), we developed an interest on the interplay between mitochondria and autophagy especially in the heart, where we identified the role of mitochondrial fusion to sustain cardiomyocyte development (Kasahara et al, Science 2013). By using a combination of specific mouse models and of biochemistry, metabolomics and cell biology we are studying how druggable regulators of autophagy and mitophagy recruit mitochondrial shape in the cardiomyocyte to exert their cardioprotective effects (Lorenza Tsantsizi) and we are defining how Opa1 defect contribute to cardiomyopathy and to ischemia-reperfusion damage (Martina Semenzato)
Is mitochondrial remodeling important in metabolism?
Our discovery that cristae shape defines efficiency of mitochondrial respiration (Cogliati et al., Cell 2013) and of mitochondria-dependent cell growth inspired us to study the role of mitochondrial remodeling in the context of metabolism, diabetes and obesity. By combining genetics, biochemistry, whole body physiology we are interested defining the role of mitochondrial shape in adipose tissue differentiation, expansion, plasticity and maintenance (Camilla Bean and Marta Medaglia). Furthermore, we are addressing how shape changes are essential to activate mitochondrial fatty acid metabolism to limit growth of intracellular parasites auxotrophic for host cell fatty acids (Lena Pernas).
What is the role of mitochondrial shape in cancer?
Since our original discovery that cristae remodeling is essential for the complete release of cytochrome c, we developed a program to investigate the role of Opa1 in cancer. We generated mice where Opa1 was overexpressed in the context of the well-known lymphoma driver Emu-Myc and found that the mild Opa1 overexpression increases severity of the disease and decreases survival, by favoring multisytemic spreading of lymphoma with severe cancer infiltrates in multiple organs (Dijana Samardzic). Because our genomic and epigenomic data indicate that Opa1 is up-regulated in melanoma cells characterized by high invasiveness potential and this up-regulation was confirmed in primary tumor samples, we generated mice lacking Opa1 in melanocytes and found that these mice display a pigmentation defect, substantiating a crucial role for Opa1 in melanocyte survival, similar to that of Bcl-2 (Akiko Omori). Finally, we are exploring the essential role of endothelial Opa1 and Drp1 in cancer angiogenesis and metastasis (Stephanie Herkenne and Maya Chergova), in lung cancer (Masa Noguchi) and developing by capitalizing on in house chemical biology screenings first in class Opa1 inhibitors (Anna Pellattiero and Margherita Zamberlan)
What are the molecular mechanisms and physiological consequences of ER-mitochondria tethering?
Since our discovery of the ER-mitochondria tethering function of Mfn2 (Brito&Scorrano, Nature 2008) we have been deepening our knowledge of the structural components of the ER-mitochondria interface (Naon et al, PNAS 2016). We are now analyzing the hits from a genome wide, FRET sensor based screening for ER-mitochondria tethers and compartments (Isotta Lorenzi, in collaboration with Marta Giacomello, University of Padua) and we are characterizing the molecular mechanism of ER-mitochondria tethering by Mfn2 (Deborah Naon and Keitaro Shibata).
- R Quintana-Cabrera, C Quirin, C Glytsou, M Corrado, A Urbani, A Pellattiero, E Calvo, J Vázquez, JA Enríquez, C Gerle, ME Soriano, P Bernardi, L. Scorrano, The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function Nat. Commun 24; 9:3399. (2018)
- L. Pernas, C. Bean, J.C. Boothroyd, L. Scorrano, Mitochondria Restrict Growth of the Intracellular Parasite Toxoplasma gondii by Limiting Its Uptake of Fatty Acids, Cell Metab., 27:886-897 (2018).
- Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, Serafini A, Semenzato M, Herkenne S, Hernández-Alvarez MI, Zorzano A, De Stefani D, Dorn GW 2nd, Scorrano L. Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci U S A. 113:11249-11254. (2016)
- G Civiletto*, T Varanita*, Cerutti R, Gorletta T, Barbaro S, Marchet S, Lamperti C, Viscomi C and L. Scorrano‡, M. Zeviani‡. ‡corresponding authors Opa1 overexpression ameliorates the clinical phenotype of two mitochondrial disease mouse models Cell Metab. 21:845-54 (2015)
- T. Varanita, M.E. Soriano, V. Romanello, T. Zaglia, R. Quintana Cabrera, M. Semenzato, R. Menabò, V. Costa, G. Civiletto, P. Pesce, C. Viscomi, M. Zeviani, F. Di Lisa, M. Mongillo, M. Sandri, and L. Scorrano The Opa1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic and ischemic tissue damage Cell Metab. 21:834-44 (2015)
- A Pyakurel, C. Savoia, D. Hess and L. Scorrano Extracellular regulated kinase phosphorylates Mitofusin 1 to control mitochondrial morphology and apoptosis. Mol. Cell, 58:244-54 (2015)
- A. Kasahara, S. Cipolat, Y. Chen, and G.W. Dorn 2nd, L. Scorrano. (2013) Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling. Science 342:734-7
- S. Cogliati, C. Frezza, M.E. Soriano, T. Varanita, R. Quintana Cabrera, M. Corrado, S. Cipolat, V. Costa, A. Casarin, L.C. Gomes, E. Perales-Clemente, L. Salviati, P. Fernandez-Silva, and J.A. Enriquez, L. Scorrano. (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell;155:160-71
- L. Gomes, G. Di Benedetto and L. Scorrano During autophagy mitochondria elongate, are spared from degradation and sustain cell viability Nat. Cell. Biol. 13:589–598 (2011)
- O. Martins de Brito and L. Scorrano Mitofusin 2 tethers mitochondria and endoplasmic reticulum. Nature 456:605-10 (2008).
- MD: University of Padova Medical School, Italy (1996)
- PhD: Dept. of Biomedical Sciences, University of Padova (2000)
- Postdoc: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA (2000-2003)
- Group leader: Assistant Telethon Scientist, Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy (2003-2006)
- Professor: Dept. of Physiology and Metabolism, University of Geneva Medical School, Geneva (Switzerland) (2007-2013)
- Professor of Biochemistry, Dept. of Biology, University of Padova (since 2013)
- Scientific Director, VIMM (since 2014)
- ESCI Award for Excellence in Basic/Translational Research, European Society for Clinical Investigation (2013)
- Elected Member, EMBO (2012)
- Eppendorf European Young Investigator Award, Eppendorf-Nature (2006)
- EMBO Young Investigator (2006)
- Career Development Award, HFSP (2004)