THERAPEUTIC STRATEGIES TO COMBAT MITOCHONDRIAL DISORDERS

The aim of the research

Main researcher

LUCA SCORRANO

Partners

MASSIMO ZEVIANI

Mitochondrial Disorders are a group of genetic maladies characterized by dysfunction of oxidative phosphorylation (OXPHOS), the energy-supplying metabolic pathway carried out by the mitochondrial respiratory chain (MRC) complexes.

Thirteen MRC protein subunits are encoded by mtDNA, which adds to the genetic, functional and structural complexity of OXPHOS, and of its disorders as well. The heterogeneity of mitochondrial disorders makes the identification of effective therapy an exceedingly difficult task. However, the elucidation of many of the pathophysiological features of these conditions give us now several clues for the development of therapeutic strategies, with the ultimate goal to cure mitochondrial disease. The most frequent biochemical abnormalities in mitochondrial disorders include isolated defects of complex I (cI) or of complex IV (cIV), and combined defects of both. The MitCare Telethon Consortium will test approved and new chemical compounds, gene and cell replacement, and a combination of these treatments, in different conditions and on systems of increasing complexity, that is, cell lines, animal models, and patients. To implement this program, MitCare will deploy three workpackages (WP). WP1 will exploit an array of patient-derived cell lines with specific biochemical defects, that will be tested using drugs involved in mitobiogenesis, calcium signaling, ROS and toxic buffering, and antiapoptotic agents. WP2, will exploit several mouse models corresponding to specific human mitochondrial disorders to test the effects of the same compounds used in WP1, or of the expression of genes able to by-pass cI or cIV defects. WP3, will test the efficacy of approved compounds targeting the same pathways as in WP1 and WP2 in patients with Leber's hereditary optic neuropathy (LHON), dominant optic atrophy (DOA) and ethylmalonic encephalopathy (EE). Validated therapies will then be extended to patients affected by other mitochondrial disorders.

Scientific publications

2015 AMERICAN JOURNAL OF NEURORADIOLOGY
Diffusion Tensor Imaging Mapping of Brain White Matter Pathology in Mitochondrial Optic Neuropathies
Manners, DN; Rizzo, G; La Morgia, C; Tonon, C; Testa, C; Barboni, P; Malucelli, E; Valentino, ML; Caporali, L; Strobbe, D; Carelli, V; Lodi, RCites: 1 (*)
2015 BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Structure and function of the mitochondrial calcium uniporter complex
De Stefani, D; Patron, M; Rizzuto, RCites: 10 (*)
2015 CELL METABOLISM
Mitochondrial Fission and Fusion Factors Reciprocally Orchestrate Mitophagic Culling in Mouse Hearts and Cultured Fibroblasts
Song, MS; Mihara, K; Chen, Y; Scorrano, L; Dorn, GWCites: 28 (*)
2015 CELL REPORTS
The Mitochondrial Calcium Uniporter Controls Skeletal Muscle Trophism In Vivo
Mammucari, C; Gherardi, G; Zamparo, I; Raffaello, A; Boncompagni, S; Chemello, F; Cagnin, S; Braga, A; Zanin, S; Pallafacchina, G; Zentilin, L; Sandri, M; De Stefani, D; Protasi, F; Lanfranchi, G; Rizzuto, RCites: 7 (*)
2015 CELL METABOLISM
The Opa1-Dependent Mitochondrial Cristae Remodeling Pathway Controls Atrophic, Apoptotic, and Ischemic Tissue Damage
Varanita, T; Soriano, ME; Romanello, V; Zaglia, T; Quintana-Cabrera, R; Semenzato, M; Menabo, R; Costa, V; Civiletto, G; Pesce, P; Viscomi, C; Zeviani, M; Di Lisa, F; Mongillo, M; Sandri, M; Scorrano, LCites: 19 (*)
2015 CELL METABOLISM
Opa1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models
Civiletto, G; Varanita, T; Cerutti, R; Gorletta, T; Barbaro, S; Marchet, S; Lamperti, C; Viscomi, C; Scorrano, L; Zeviani, MCites: 16 (*)
2015 JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
The mitochondrial permeability transition pore: Molecular nature and role as a target in cardioprotection
Bernardi, P; Di Lisa, FCites: 41 (*)
2014 MOLECULAR THERAPY
Gene Therapy Using a Liver-targeted AAV Vector Restores Nucleoside and Nucleotide Homeostasis in a Murine Model of MNGIE
Torres-Torronteras, J; Viscomi, C; Cabrera-Perez, R; Camara, Y; Di Meo, I; Barquinero, J; Auricchio, A; Pizzorno, G; Hirano, M; Zeviani, M; Marti, RCites: 3 (*)
2014 MOVEMENT DISORDERS
Myoclonus in Mitochondrial Disorders
Mancuso, M; Orsucci, D; Angelini, C; Bertini, E; Catteruccia, M; Pegoraro, E; Carelli, V; Valentino, ML; Comi, GP; Minetti, C; Bruno, C; Moggio, M; Ienco, EC; Mongini, T; Vercelli, L; Primiano, G; Servidei, S; Tonin, P; Scarpelli, M; Toscano, A; Musumeci, O; Moroni, I; Uziel, G; Santorelli, FM; Nesti, C; Filosto, M; Lamperti, C; Zeviani, M; Siciliano, GCites: 1 (*)
2014 JOURNAL OF NEUROLOGY
The m.3243A > G mitochondrial DNA mutation and related phenotypes. A matter of gender?
Mancuso, M; Orsucci, D; Angelini, C; Bertini, E; Carelli, V; Comi, GP; Donati, A; Minetti, C; Moggio, M; Mongini, T; Servidei, S; Tonin, P; Toscano, A; Uziel, G; Bruno, C; Ienco, EC; Filosto, M; Lamperti, C; Catteruccia, M; Moroni, I; Musumeci, O; Pegoraro, E; Ronchi, D; Santorelli, FM; Sauchelli, D; Scarpelli, M; Sciacco, M; Valentino, ML; Vercelli, L; Zeviani, M; Siciliano, GCites: 4 (*)
2014 NEUROLOGY
Novel (ovario) leukodystrophy related to AARS2 mutations
Dallabona, C; Diodato, D; Kevelam, SH; Haack, TB; Wong, LJ; Salomons, GS; Baruffini, E; Melchionda, L; Mariotti, C; Strom, TM; Meitinger, T; Prokisch, H; Chapman, K; Colley, A; Rocha, H; Ounap, K; Schiffmann, R; Salsano, E; Savoiardo, M; Hamilton, EM; AbbCites: 4 (*)
2014 MOLECULAR THERAPY
AAV-mediated Liver-specific MPV17 Expression Restores mtDNA Levels and Prevents Diet-induced Liver Failure
Bottani, E; Giordano, C; Civiletto, G; Di Meo, I; Auricchio, A; Ciusani, E; Marchet, S; Lamperti, C; d'Amati, G; Viscomi, C; Zeviani, MCites: 1 (*)
2014 NATURE GENETICS
Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling
Logan, CV; Szabadkai, G; Sharpe, JA; Parry, DA; Torelli, S; Childs, AM; Kriek, M; Phadke, R; Johnson, CA; Roberts, NY; Bonthron, DT; Pysden, KA; Whyte, T; Munteanu, I; Foley, AR; Wheway, G; Szymanska, K; Natarajan, S; Abdelhamed, ZA; Morgan, JE; Roper, H; Santen, GWE; Niks, EH; van der Pol, WL; Lindhout, D; Raffaello, A; De Stefani, D; den Dunnen, JT; Sun, Y; Ginjaar, I; Sewry, CA; Hurles, M; Rizzuto, R; Duchen, MR; Muntoni, F; Sheridan, E; UK10K ConsortiumCites: 19 (*)
2014 JOURNAL OF BIOLOGICAL CHEMISTRY
Functional Characterization of drim2, the Drosophila melanogaster Homolog of the Yeast Mitochondrial Deoxynucleotide Transporter
Da-Re, C; Franzolin, E; Biscontin, A; Piazzesi, A; Pacchioni, B; Gagliani, MC; Mazzotta, G; Tacchetti, C; Zordan, MA; Zeviani, M; Bernardi, P; Bianchi, V; De Pitta, C; Costa, RCites: 2 (*)
2014 MOLECULAR CELL
MICU1 and MICU2 Finely Tune the Mitochondrial Ca2+ Uniporter by Exerting Opposite Effects on MCU Activity
Patron, M; Checchetto, V; Raffaello, A; Teardo, E; Reane, DV; Mantoan, M; Granatiero, V; Szabo, I; De Stefani, D; Rizzuto, RCites: 16 (*)
2014 CELL METABOLISM
NAD+-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease
Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve A, Li W, Leoni V, Schon EA, Dantzer F, Auwerx J, Viscomi C, Zeviani MCites: 11 (*)
2014 BRAIN
Efficient mitochondrial biogenesis drives incomplete penetrance in Lebers hereditary optic neuropathy
Giordano C; Iommarini L; Giordano L; Maresca A; Pisano A; Valentino ML; Caporali L; Liguori R; Deceglie S; Roberti M; Fanelli F; Fracasso F; Ross-Cisneros FN; D'Adamo P; Hudson G; Pyle A; Yu-Wai-Man P; Chinnery PF; Zeviani M; Salomao SR; Berezovsky A; Belfort R; Ventura DF; Moraes M; Moraes M; Barboni P; Sadun F; De Negri A; Sadun AA; Tancredi A; Mancini M; d'Amati G; Polosa PL; Cantatore P; Carelli VCites: 8 (*)
2013 EMBO JOURNAL
The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit
Raffaello, A; De Stefani, D; Sabbadin, D; Teardo, E; Merli, G; Picard, A; Checchetto, V; Moro, S; Szabo, I; Rizzuto, RCites: 30 (*)
2013 LANCET NEUROLOGY
Peripheral neuropathy in mitochondrial disorders
Pareyson, D; Piscosquito, G; Moroni, I; Salsano, E; Zeviani, MCites: 5 (*)
2013 SCIENCE
Mitochondrial Fusion Directs Cardiomyocyte Differentiation via Calcineurin and Notch Signaling
Kasahara, A; Cipolat, S; Chen, Y; Dorn, GW; Scorrano, LCites: 32 (*)
2013 CELL
Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency
Cogliati, S; Frezza, C; Soriano, ME; Varanita, T; Quintana-Cabrera, R; Corrado, M; Cipolat, S; Costa, V; Casarin, A; Gomes, LC; Perales-Clemente, E; Salviati, L; Fernandez-Silva, P; Enriquez, JA; Scorrano, LCites: 45 (*)
2013 FASEB JOURNAL
Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity
Deepa, SS; Pulliam, D; Hill, S; Shi, Y; Walsh, ME; Salmon, A; Sloane, L; Zhang, N; Zeviani, M; Viscomi, C; Musi, N; Van Remmen, HCites: 6 (*)
2013 MOLECULAR AND CELLULAR NEUROSCIENCE
The optic nerve: A mito-window on mitochondrial neurodegeneration
Maresca, A; la Morgia, C; Caporali, L; Valentino, ML; Carelli, VCites: 11 (*)
2013 PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Frequency-dependent mitochondrial Ca2+ accumulation regulates ATP synthesis in pancreatic beta cells
Tarasov, AI; Semplici, F; Li, DL; Rizzuto, R; Ravier, MA; Gilon, P; Rutter, GACites: 10 (*)
2013 JOURNAL OF BIOLOGICAL CHEMISTRY
The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles
Patron, M; Raffaello, A; Granatiero, V; Tosatto, A; Merli, G; De Stefani, D; Wright, L; Pallafacchina, G; Terrin, A; Mammucari, C; Rizzuto, RCites: 20 (*)
2013 ORPHANET JOURNAL OF RARE DISEASES
Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant
Melchionda, L; Fang, MY; Wang, HR; Fugnanesi, V; Morbin, M; Liu, XZ; Li, WY; Ceccherini, I; Farina, L; Savoiardo, M; DAdamo, P; Zhang, JG; Costa, A; Ravaglia, S; Ghezzi, D; Zeviani, MCites: 2 (*)
2012 PLOS ONE
Rare Primary Mitochondrial DNA Mutations and Probable Synergistic Variants in Lebers Hereditary Optic Neuropathy
Achilli, A; Iommarini, L; Olivieri, A; Pala, M; Kashani, BH; Reynier, P; La Morgia, C; Valentino, ML; Liguori, R; Pizza, F; Barboni, P; Sadun, F; De Negri, AM; Zeviani, M; Dollfus, H; Moulignier, A; Ducos, G; Orssaud, C; Bonneau, D; Procaccio, V; Leo-KottCites: 11 (*)
2012 NATURE REVIEWS MOLECULAR CELL BIOLOGY
Mitochondria as sensors and regulators of calcium signalling
Rizzuto, R; De Stefani, D; Raffaello, A; Mammucari, CCites: 147 (*)
2012 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AME
Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes
Drago, I; De Stefani, D; Rizzuto, R; Pozzan, TCites: 27 (*)
2012 CELL CALCIUM
The mitochondrial Ca2+ uniporter
Raffaello, A; De Stefani, D; Rizzuto, RCites: 19 (*)
2012 PLOS ONE
The Mitochondrial Ca2+ Uniporter MCU Is Essential for Glucose-Induced ATP Increases in Pancreatic beta-Cells
Tarasov, AI; Semplici, F; Ravier, MA; Bellomo, EA; Pullen, TJ; Gilon, P; Sekler, I; Rizzuto, R; Rutter, GACites: 29 (*)
2012 NEUROMUSCULAR DISORDERS
MELAS-like encephalomyopathy caused by a new pathogenic mutation in the mitochondrial DNA encoded cytochrome c oxidase subunit I
Lamperti, C; Diodato, D; Lamantea, E; Carrara, F; Ghezzi, D; Mereghetti, P; Rizzi, R; Zeviani, MCites: 1 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Cowchock Syndrome Is Associated with a Mutation in Apoptosis-Inducing Factor
Rinaldi, C; Grunseich, C; Sevrioukova, IF; Schindler, A; Horkayne-Szakaly, I; Lamperti, C; Landoure, G; Kennerson, ML; Burnett, BG; Bonnemann, C; Biesecker, LG; Ghezzi, D; Zeviani, M; Fischbeck, KHCites: 14 (*)
2012 NEUROMUSCULAR DISORDERS
Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases
Mancuso, M; Angelini, C; Bertini, E; Carelli, V; Comi, GP; Minetti, C; Moggio, M; Mongini, T; Servidei, S; Tonin, P; Toscano, A; Uziel, G; Zeviani, M; Siciliano, G; Nation Wide Italian CollaborativeCites: 2 (*)
2012 NEUROMUSCULAR DISORDERS
Partial tandem duplication of mtDNA-tRNA(Phe) impairs mtDNA translation in late-onset mitochondrial myopathy
Arzuffi, P;Lamperti, C;Fernandez-Vizarra, E;Tonin, P;Morandi, L;Zeviani, MCites: 1 (*)
2012 MITOCHONDRION
Microscale oxygraphy reveals OXPHOS impairment in MRC mutant cells
Invernizzi, F;DAmato, I;Jensen, PB;Ravaglia, S;Zeviani, M;Tiranti, VCites: 19 (*)
2012 CELL DEATH AND DIFFERENTIATION
VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria
De Stefani, D; Bononi, A; Romagnoli, A; Messina, A; De Pinto, V; Pinton, P; Rizzuto, RCites: 38 (*)
2012 JOURNAL OF MEDICAL GENETICS
Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9
Haack, TB;Madignier, F;Herzer, M;Lamantea, E;Danhauser, K;Invernizzi, F;Koch, J;Freitag, M;Drost, R;Hillier, I;Haberberger, B;Mayr, JA;Ahting, U;Tiranti, V;Rotig, A;Iuso, A;Horvath, R;Tesarova, M;Baric, I;Uziel, G;Rolinski, B;Sperl, W;Meitinger, T;Zeviani, M;Freisinger, P;Prokisch, HCites: 16 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Lack of the Mitochondrial Protein Acylglycerol Kinase Causes Sengers Syndrome
Mayr, JA;Haack, TB;Graf, E;Zimmermann, FA;Wieland, T;Haberberger, B;Superti-Furga, A;Kirschner, J;Steinmann, B;Baumgartner, MR;Moroni, I;Lamantea, E;Zeviani, M;Rodenburg, RJ;Smeitink, J;Strom, TM;Meitinger, T;Sperl, W;Prokisch, HCites: 42 (*)
2012 CELL CYCLE
The selective inhibition of nuclear PKC zeta restores the effectiveness of chemotherapeutic agents in chemoresistant cells
Rimessi, A;Zecchini, E;Siviero, R;Giorgi, C;Leo, S;Rizzuto, R;Pinton, PCites: 1 (*)
2012 JOURNAL OF INHERITED METABOLIC DISEASE
Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy
Giordano, C;Viscomi, C;Orlandi, M;Papoff, P;Spalice, A;Burlina, A;Di Meo, I;Tiranti, V;Leuzzi, V;dAmati, G;Zeviani, MCites: 10 (*)
2012 EMBO MOLECULAR MEDICINE
Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy
Di Meo, I; Auricchio, A; Lamperti, C; Burlina, A; Viscomi, C; Zeviani, MCites: 9 (*)
2012 AMERICAN JOURNAL OF HUMAN GENETICS
Mutations in COX7B Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease
Indrieri, A; van Randen, VA; Tiranti, V; Morleo, M; Iaconis, D; Tammaro, R; DAmato, I; Conte, I; Maystadt, I; Demuth, S; Zvulunov, A; Kutsche, K; Zeviani, M; Franco, BCites: 20 (*)
2012 JOURNAL OF MEDICAL GENETICS
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing
Haack, TB; Haberberger, B; Frisch, EM; Wieland, T; Iuso, A; Gorza, M; Strecker, V; Graf, E; Mayr, JA; Herberg, U; Hennermann, JB; Klopstock, T; Kuhn, KA; Ahting, U; Sperl, W; Wilichowski, E; Hoffmann, GF; Tesarova, M; Hansikova, H; Zeman, J; Plecko, B; Zeviani, M; Wittig, I; Strom, TM; Schuelke, M; Freisinger, P; Meitinger, T; Prokisch, HCites: 35 (*)
2012 BRAIN
Leukoencephalopathy with thalamus and brainstem involvement and high lactate LTBL caused by EARS2 mutations
Steenweg, ME; Ghezzi, D; Haack, T; Abbink, TEM; Martinelli, D; van Berkel, CGM; Bley, A; Diogo, L; Grillo, E; Naude, JTW; Strom, TM; Bertini, E; Prokisch, H; van der Knaap, MS; Zeviani, MCites: 50 (*)
2012 SAUDI J GASTROENTERO
Hepatocerebral form of mitochondrial DNA depletion syndrome due to mutation in MPV17 gene
AlSaman, A; Tomoum, H; Invernizzi, F; Zeviani, MCites: 6 (*)
2012 MOLECULAR GENETICS AND METABOLISM
A novel homozygous mutation in SUCLA2 gene identified by exome sequencing
Lamperti, C; Fang, MY; Invernizzi, F; Liu, XZ; Wang, HR; Zhang, Q; Carrara, F; Moroni, I; Zeviani, M; Zhang, JG; Ghezzi, DCites: 13 (*)
2012 BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
The effects of idebenone on mitochondrial bioenergetics
Giorgio, V; Petronilli, V; Ghelli, A; Carelli, V; Rugolo, M; Lenaz, G; Bernardi, PCites: 23 (*)
2011 CELL
Traveling Bax and forth from mitochondria to control apoptosis
Soriano ME; Scorrano LCites: 19 (*)
2011 NATURE GENETICS
Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies
Ghezzi, D; Arzuffi, P; Zordan, M; Da Re, C; Lamperti, C; Benna, C; DAdamo, P; Diodato, D; Costa, R; Mariotti, C; Uziel, G; Smiderle, C; Zeviani, MCites: 38 (*)
2011 CELL METABOLISM
In Vivo Correction of COX Deficiency by Activation of the AMPK/PGC-1 alpha Axis
Viscomi, C; Bottani, E; Civiletto, G; Cerutti, R; Moggio, M; Fagiolari, G; Schon, EA; Lamperti, C; Zeviani, MCites: 68 (*)
2011 SEMINARS IN FETAL & NEONATAL MEDICINE
Infantile mitochondrial encephalopathy
Uziel, G; Ghezzi, D; Zeviani, MCites: 10 (*)
2011 NATURE
A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter
De Stefani, D; Raffaello, A; Teardo, E; Szabo, I; Rizzuto, RCites: 330 (*)