411 results on '"Caporali, Leonardo"'
Search Results
102. Somatic mutation profiling of hobnail variant of papillary thyroid carcinoma
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Morandi, Luca, primary, Righi, Alberto, additional, Maletta, Francesca, additional, Rucci, Paola, additional, Pagni, Fabio, additional, Gallo, Marco, additional, Rossi, Sabrina, additional, Caporali, Leonardo, additional, Sapino, Anna, additional, Lloyd, Ricardo V, additional, and Asioli, Sofia, additional
- Published
- 2017
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103. Reply to: "Lack of Association between TWNK Rare Variants and Parkinson's Disease in a Chinese Cohort".
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Percetti, Marco, Monfrini, Edoardo, Caporali, Leonardo, Minardi, Raffaella, Carelli, Valerio, Valente, Enza Maria, and Di Fonzo, Alessio
- Published
- 2023
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104. HPLC-UV analysis of thymidine and deoxyuridine in plasma of patients with thymidine phosphorylase deficiency
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Mohamed, Susan, Caporali, Leonardo, De Giorgio, Roberto, Carelli, Valerio, and Contin, Manuela
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- 2014
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105. Mitochondrial abnormalities in fibroblasts carrying DNMT1 mutations
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MARESCA, ALESSANDRA, ZANNA, CLAUDIA, CAPORALI, LEONARDO, PIZZA, FABIO, LA MORGIA, CHIARA, PLAZZI, GIUSEPPE, CARELLI, VALERIO, Del Dotto V, Moghadam KK, Melberg A, Mignot E, Maresca A, Zanna C, Del Dotto V, Caporali L, Moghadam KK, Pizza F, La Morgia C, Melberg A, Mignot E, Plazzi G, and Carelli V
- Abstract
Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) and hereditary sensory neuropathy with dementia and hearing loss (HSE-IN) are rare neurodegenerative syndromes recently linked to dominant pathogenic mutations in the DNA methyltransferase 1 (DNMT1) gene. ADCA-DN and HSN-IE phenotypes share some features such as optic atrophy, deafness, cerebellar ataxia, peripheral neuropathy and narcolepsy. Moreover, both ADCA-DN and HSN-IE phenotypes present clinical features typical of mitochondrial diseases and some biochemical evidence of mitochondrial dysfunction in muscle of ADCA-DN patients was previously reported. Interestingly, DNMT1 has been recently recognized as responsible for mitochondrial DNA (mtDNA) methylation, in addition to nuclear DNA methylation, suggesting that DNMT1 mutations may directly affect mtDNA, supporting also the hypothesis of mitochondrial dysfunction in ADCA-DN and HSN-IE. To investigate the pathogenic mechanisms of DNMT1 mutations, and how these genetic defects may affect mitochondrial function, we studied fibroblasts from ADCA-DN and HSE-IN families carrying four different mutations in DNMT1 (p.A570V, p.G605A, p.V606F, p.P507R). All mutants showed a significant increase of about 1,5 fold in DNMT1 mRNA expression and a significant reduction of about 40% in the global DNA methyltransferase activity, as evaluated in total cellular protein extracts, compared to controls. Analysis of mitochondrial transcription revealed a significant increase of mitochondrial gene expression in the mutants compared to controls. We observed the mitochondrial network after 48 hours of growth in galactose medium, finding a marked decrease in the percentage of cells with filamentous mitochondria and, concomitantly, an increased number of cells with fragmented mitochondria. These preliminary data demonstrate that mutations in DNMT1 responsible for ADCA-DN and HSE-IN may produce a defect in the methyltransferase activity, possibly causing a reduction in mtDNA methylation, which in turn leads to the increased mtDNA transcription. Moreover, the network fragmentation induced by galactose suggests a mitochondrial defect impinging on the mito-network dynamics.
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- 2014
106. Reply to: No Association between Rare TWNK Variants and Parkinson's Disease in European Cohorts.
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Percetti, Marco, Monfrini, Edoardo, Caporali, Leonardo, Minardi, Raffaella, Carelli, Valerio, Valente, Enza Maria, and Di Fonzo, Alessio
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PROTEINS ,RESEARCH funding ,PARKINSON'S disease ,GENETIC mutation - Published
- 2022
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107. Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy
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De Giorgio, Roberto, primary, Pironi, Loris, additional, Rinaldi, Rita, additional, Boschetti, Elisa, additional, Caporali, Leonardo, additional, Capristo, Mariantonietta, additional, Casali, Carlo, additional, Cenacchi, Giovanna, additional, Contin, Manuela, additional, D'Angelo, Roberto, additional, D'Errico, Antonietta, additional, Gramegna, Laura Ludovica, additional, Lodi, Raffaele, additional, Maresca, Alessandra, additional, Mohamed, Susan, additional, Morelli, Maria Cristina, additional, Papa, Valentina, additional, Tonon, Caterina, additional, Tugnoli, Vitaliano, additional, Carelli, Valerio, additional, D'Alessandro, Roberto, additional, and Pinna, Antonio Daniele, additional
- Published
- 2016
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108. Pharmacogenetics and Treatment Response in Narcolepsy Type 1
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Moresco, Monica, primary, Riccardi, Laura Natalia, additional, Pizza, Fabio, additional, Zenesini, Corrado, additional, Caporali, Leonardo, additional, Plazzi, Giuseppe, additional, and Pelotti, Susi, additional
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- 2016
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109. Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion
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Carelli, Valerio, primary, d’Adamo, Pio, additional, Valentino, Maria Lucia, additional, La Morgia, Chiara, additional, Ross-Cisneros, Fred N., additional, Caporali, Leonardo, additional, Maresca, Alessandra, additional, Loguercio Polosa, Paola, additional, Barboni, Piero, additional, De Negri, Annamaria, additional, Sadun, Federico, additional, Karanjia, Rustum, additional, Salomao, Solange R., additional, Berezovsky, Adriana, additional, Chicani, Filipe, additional, Moraes, Milton, additional, Moraes Filho, Milton, additional, Belfort, Rubens, additional, and Sadun, Alfredo A., additional
- Published
- 2015
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110. SCN1Amutations in focal epilepsy with auditory features: widening the spectrum of GEFS plus
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Bisulli, Francesca, Licchetta, Laura, Baldassari, Sara, Muccioli, Lorenzo, Marconi, Caterina, Cantalupo, Gaetano, Myers, Candace, Menghi, Veronica, Minardi, Raffaella, Caporali, Leonardo, Marini, Carla, Guerrini, Renzo, Mefford, Heather C., Tinuper, Paolo, and Pippucci, Tommaso
- Abstract
Aims. Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1Amissense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus(GEFS+). We aimed to investigate the role/impact of SCN1Amutations in EAF. Methods. We detailed the phenotype of this family and report on SCN1Ascreening in a cohort of 29 familial and 52 sporadic LGI1variant‐negative EAF patients. Results. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. Conclusion. SCN1Amutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1Ain EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.
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- 2019
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111. An Ugo1-like protein is associated with optic atrophy ‘plus’ disorders
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Abrams, Alexander J., primary, Hufnagel, Robert B., additional, Rebelo, Adriana, additional, Zanna, Claudia, additional, Patel, Neville, additional, Gonzalez, Michael A., additional, Campeanu, Ion J., additional, Griffin, Laurie B., additional, Groenewald, Saskia, additional, Strickland, Alleene V., additional, Tao, Feifei, additional, Speziani, Fiorella, additional, Caporali, Leonardo, additional, La Morgia, Chiara, additional, Liguori, Rocco, additional, Lodi, Raffaele, additional, Ahmed, Zubair M., additional, Sund, Kristen L., additional, Wang, Xinjian, additional, Krueger, Laura A., additional, Peng, Yanyan, additional, Prada, Carlos E., additional, Prows, Cynthia A., additional, Bove, Kevin, additional, Schorry, Elizabeth K., additional, Antonellis, Anthony, additional, Zimmerman, Holly H., additional, Abdulrahman, Omar A., additional, Yang, Yaping, additional, Downes, Susan M., additional, Prince, Jeffery, additional, Nemeth, Andrea H., additional, Carelli, Valerio, additional, Huang, Taosheng, additional, Julia, Dallman, additional, and Zuchner, Stephan, additional
- Published
- 2015
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112. Syndromic parkinsonism and dementia associated withOPA1 missense mutations
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Carelli, Valerio, primary, Musumeci, Olimpia, additional, Caporali, Leonardo, additional, Zanna, Claudia, additional, La Morgia, Chiara, additional, Del Dotto, Valentina, additional, Porcelli, Anna Maria, additional, Rugolo, Michela, additional, Valentino, Maria Lucia, additional, Iommarini, Luisa, additional, Maresca, Alessandra, additional, Barboni, Piero, additional, Carbonelli, Michele, additional, Trombetta, Costantino, additional, Valente, Enza Maria, additional, Patergnani, Simone, additional, Giorgi, Carlotta, additional, Pinton, Paolo, additional, Rizzo, Giovanni, additional, Tonon, Caterina, additional, Lodi, Raffaele, additional, Avoni, Patrizia, additional, Liguori, Rocco, additional, Baruzzi, Agostino, additional, Toscano, Antonio, additional, and Zeviani, Massimo, additional
- Published
- 2015
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113. Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations
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Carelli, Valerio, primary, Maresca, Alessandra, additional, Caporali, Leonardo, additional, Trifunov, Selena, additional, Zanna, Claudia, additional, and Rugolo, Michela, additional
- Published
- 2015
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114. Early Macular Retinal Ganglion Cell Loss in Dominant Optic Atrophy: Genotype-Phenotype Correlation
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Barboni, Piero, primary, Savini, Giacomo, additional, Cascavilla, Maria Lucia, additional, Caporali, Leonardo, additional, Milesi, Jacopo, additional, Borrelli, Enrico, additional, La Morgia, Chiara, additional, Valentino, Maria Lucia, additional, Triolo, Giacinto, additional, Lembo, Andrea, additional, Carta, Arturo, additional, De Negri, Annamaria, additional, Sadun, Federico, additional, Rizzo, Giovanni, additional, Parisi, Vincenzo, additional, Pierro, Luisa, additional, Bianchi Marzoli, Stefania, additional, Zeviani, Massimo, additional, Sadun, Alfredo A., additional, Bandello, Francesco, additional, and Carelli, Valerio, additional
- Published
- 2014
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115. ‘Behr syndrome’ with OPA1 compound heterozygote mutations
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Carelli, Valerio, primary, Sabatelli, Mario, additional, Carrozzo, Rosalba, additional, Rizza, Teresa, additional, Schimpf, Simone, additional, Wissinger, Bernd, additional, Zanna, Claudia, additional, Rugolo, Michela, additional, La Morgia, Chiara, additional, Caporali, Leonardo, additional, Carbonelli, Michele, additional, Barboni, Piero, additional, Tonon, Caterina, additional, Lodi, Raffaele, additional, and Bertini, Enrico, additional
- Published
- 2014
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116. Impaired mitochondrial energetic function and altered supramolecular interactions of respiratory chain complexes in cells bearing a novel pathogenic cytochrome b microdeletion
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Rugolo, Michela, primary, Tropeano, Concetta Valentina, additional, Calvaruso, Maria Antonietta, additional, Caporali, Leonardo, additional, Carelli, Valerio, additional, Daldal, Fevzi, additional, and Ghelli, Anna Maria, additional
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- 2014
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117. A Novel in-Frame 18-bp Microdeletion inMT-CYBCauses a Multisystem Disorder with Prominent Exercise Intolerance
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Carossa, Valeria, primary, Ghelli, Anna, additional, Tropeano, Concetta Valentina, additional, Valentino, Maria Lucia, additional, Iommarini, Luisa, additional, Maresca, Alessandra, additional, Caporali, Leonardo, additional, La Morgia, Chiara, additional, Liguori, Rocco, additional, Barboni, Piero, additional, Carbonelli, Michele, additional, Rizzo, Giovanni, additional, Tonon, Caterina, additional, Lodi, Raffaele, additional, Martinuzzi, Andrea, additional, De Nardo, Vera, additional, Rugolo, Michela, additional, Ferretti, Luca, additional, Gandini, Francesca, additional, Pala, Maria, additional, Achilli, Alessandro, additional, Olivieri, Anna, additional, Torroni, Antonio, additional, and Carelli, Valerio, additional
- Published
- 2014
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118. Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions
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La Morgia, Chiara, primary, Caporali, Leonardo, additional, Gandini, Francesca, additional, Olivieri, Anna, additional, Toni, Francesco, additional, Nassetti, Stefania, additional, Brunetto, Daniela, additional, Stipa, Carlotta, additional, Scaduto, Cristina, additional, Parmeggiani, Antonia, additional, Tonon, Caterina, additional, Lodi, Raffaele, additional, Torroni, Antonio, additional, and Carelli, Valerio, additional
- Published
- 2014
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119. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy
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Giordano, Carla, primary, Iommarini, Luisa, additional, Giordano, Luca, additional, Maresca, Alessandra, additional, Pisano, Annalinda, additional, Valentino, Maria Lucia, additional, Caporali, Leonardo, additional, Liguori, Rocco, additional, Deceglie, Stefania, additional, Roberti, Marina, additional, Fanelli, Francesca, additional, Fracasso, Flavio, additional, Ross-Cisneros, Fred N., additional, D’Adamo, Pio, additional, Hudson, Gavin, additional, Pyle, Angela, additional, Yu-Wai-Man, Patrick, additional, Chinnery, Patrick F., additional, Zeviani, Massimo, additional, Salomao, Solange R., additional, Berezovsky, Adriana, additional, Belfort, Rubens, additional, Ventura, Dora Fix, additional, Moraes, Milton, additional, Moraes Filho, Milton, additional, Barboni, Piero, additional, Sadun, Federico, additional, De Negri, Annamaria, additional, Sadun, Alfredo A., additional, Tancredi, Andrea, additional, Mancini, Massimiliano, additional, d’Amati, Giulia, additional, Loguercio Polosa, Paola, additional, Cantatore, Palmiro, additional, and Carelli, Valerio, additional
- Published
- 2013
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120. Cybrid studies establish the causal link between the mtDNA m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions
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Caporali, Leonardo, primary, Ghelli, Anna Maria, additional, Iommarini, Luisa, additional, Maresca, Alessandra, additional, Valentino, Maria Lucia, additional, La Morgia, Chiara, additional, Liguori, Rocco, additional, Zanna, Claudia, additional, Barboni, Piero, additional, De Nardo, Vera, additional, Martinuzzi, Andrea, additional, Rizzo, Giovanni, additional, Tonon, Caterina, additional, Lodi, Raffaele, additional, Calvaruso, Maria Antonietta, additional, Cappelletti, Martina, additional, Porcelli, Anna Maria, additional, Achilli, Alessandro, additional, Pala, Maria, additional, Torroni, Antonio, additional, and Carelli, Valerio, additional
- Published
- 2013
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121. Searching for genetic modifiers of Leber's hereditary optic neuropathy penetrance
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Caporali, Leonardo, primary, Giordano, Carla, additional, Iommarini, Luisa, additional, Maresca, Alessandra, additional, D'adamo, Pio, additional, Salomao, Solange R., additional, Belfort, Rubens, additional, Sadun, Alfredo, additional, and Carelli, Valerio, additional
- Published
- 2012
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122. EPI-743: Preliminary report on Italian experience in open label study of three patients with acute Leber's hereditary optic neuropathy
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Carelli, Valerio, primary, Barboni, Piero, additional, Caporali, Leonardo, additional, Maresca, Alessandra, additional, Miller, Guy, additional, and Valentino, Maria Lucia, additional
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- 2012
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123. OPAopathies: Widening the spectrum of human diseases associated with mutations in the OPA1 gene
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Caporali⁎, Leonardo, primary, Valentino, Maria Lucia, additional, Iommarini, Luisa, additional, Maresca, Alessandra, additional, Carroccia, Rosanna, additional, Carbonelli, Michele, additional, La Morgia, Chiara, additional, Tonon, Caterina, additional, Barboni, Piero, additional, Lodi, Raffaele, additional, Lamperti, Costanza, additional, Lamantea, Eleonora, additional, Zeviani, Massimo, additional, Kohl, Susanne, additional, Wissinger, Bernd, additional, Liguori, Rocco, additional, Montagna, Pasquale, additional, and Carelli, Valerio, additional
- Published
- 2011
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124. Syndromic parkinsonism and dementia associated with OPA 1 missense mutations.
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Carelli, Valerio, Musumeci, Olimpia, Caporali, Leonardo, Zanna, Claudia, La Morgia, Chiara, Del Dotto, Valentina, Porcelli, Anna Maria, Rugolo, Michela, Valentino, Maria Lucia, Iommarini, Luisa, Maresca, Alessandra, Barboni, Piero, Carbonelli, Michele, Trombetta, Costantino, Valente, Enza Maria, Patergnani, Simone, Giorgi, Carlotta, Pinton, Paolo, Rizzo, Giovanni, and Tonon, Caterina
- Abstract
Objective Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia. Methods Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements. Results Affected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase-negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy. Interpretation The association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21-38 [ABSTRACT FROM AUTHOR]
- Published
- 2015
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125. DNA methyltransferase 1 mutations and mitochondrial pathology: is mtDNA methylated?
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Maresca, Alessandra, Zaffagnini, Mirko, Caporali, Leonardo, Carelli, Valerio, and Zanna, Claudia
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DNA methyltransferases ,METHYLTRANSFERASES ,MITOCHONDRIAL pathology ,CELLULAR pathology ,DNA methylation - Abstract
Autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E) are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5)- methyltransferase 1 (DNMT1). DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy, and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA) suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however, mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is regulated and executed? [ABSTRACT FROM AUTHOR]
- Published
- 2015
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126. Cellular and metabolic changes in the liver tissue of patients with Mitochondrial Neurogastrointestinal Encephalomyopathy.
- Author
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Boschetti, Elisa, Caporali, Leonardo, D'Angelo, Roberto, Tardio, Maria Lucia, Costa, Roberta, Accarino, Anna, Malagelada, Carolina, Righi, Valeria, Costanzini, Anna, D'Errico, Antonietta, Cenacchi, Giovanna, Sternini, Catia, Stanghellini, Vincenzo, Pironi, Loris, Rinaldi, Rita, Ratti, Stefano, Manzoli, Lucia, Carelli, Valerio, and De Giorgio, Roberto
- Subjects
- *
URIDINE , *VASCULAR endothelial growth factors , *HYPOXIA-inducible factor 1 , *HEMATOXYLIN & eosin staining , *LIVER , *ENDOTHELIAL cells , *MITOCHONDRIA - Abstract
Objective: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare disease caused by a genetically-driven thymidine phosphorylase (TP) defect. TP converts the nucleosides thymidine and deoxyuridine into respective nucleotides. In MNGIE, these nucleosides accumulate promoting tissue damage and mtDNA abnormalities responsible for neurological impairment and severe gastrointestinal dysmotility. The resulting clinical phenotype has a tremendous impact on patients' poor quality of life and fatal outcome.1;2 One possible treatment strategy to MNGIE patients is the stable reduction of circulating toxic nucleosides via liver transplantation. This approach has been successfully achieved in MNGIE patients in Italy and in many Western Countries.3 Although the liver has never been described as a target organ of the disease, explanted livers of MNGIE patients show clear macroscopic changes. Aim: The objective of our study was to provide an accurate morphologic and metabolic analysis of MNGIE liver tissue vs. controls (CTR). Methods: Liver tissue biopsies (1x1 cm each sample) were collected from n=7 MNGIE (2F; 20-38 yrs) and n=7 CTR (2F; 22-67 yrs) subjects. Formalin fixed-paraffin embedded tissue sections were processed for: 1) Hematoxylin and Eosin staining to evaluate architectural changes; 2) Sirius Red/Fast Green collagen assay to localize and quantify fibrosis; 3) Orcein, vascular endothelial cells growth factor and CD31 immunostaining to assess vascular changes; 4) hypoxia-inducible-factor-1a (HIF-1a) immunostaining to test hypoxia. Part of the liver tissue biopsies (0.5x0.5 cm each sample) were collected and snap frozen from n=3 MNGIE and n=3 CTR for metabolomic NMR assay. Results: MNGIE liver was characterized by intense steatosis. Fibrosis increases (P=0.0025) with patient age leading to the formation of porto-portal and porto-central collagen septa. The vascular and biliary branches were altered and these findings correlated with the increased hypoxia in hepatocytes, as indicated by HIF-1a positive staining. Preliminary analysis performed with NMR indicated a rearrangement characterized by triglyceride production and a significant decline in aerobic metabolism. Conclusions: Our data, showing marked morphological and metabolic changes, indicate that the liver is a target organ of MNGIE. Liver alterations should be carefully taken into account as a compromised liver may interfere with the clinical response to targeted treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2021
127. ITA-MNGIE: an Italian regional and national survey for mitochondrial neuro-gastro-intestinal encephalomyopathy.
- Author
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D'Angelo, Roberto, Rinaldi, Rita, Carelli, Valerio, Boschetti, Elisa, Caporali, Leonardo, Capristo, Mariantonietta, Casali, Carlo, Cenacchi, Giovanna, Gramegna, Laura, Lodi, Raffaele, Pinna, Antonio, Pironi, Loris, Stanzani, Marta, Tonon, Caterina, D'Alessandro, Roberto, De Giorgio, Roberto, Gramegna, Laura Ludovica, and Pinna, Antonio Daniele
- Subjects
MITOCHONDRIAL neurogastrointestinal encephalopathy syndrome ,EARLY diagnosis ,ITALIANS ,THYMIDINE phosphorylase ,GENETIC mutation ,HEALTH surveys ,HEALTH ,LANGUAGE & languages ,TRANSFERASES ,MITOCHONDRIAL encephalomyopathies - Abstract
Mitochondrial neuro-gastro-intestinal encephalomyopathy (MNGIE) is a rare and unavoidably fatal disease due to mutations in thymidine phosphorylase (TP). Clinically it is characterized by gastrointestinal dysfunction, malnutrition/cachexia and neurological manifestations. MNGIE diagnosis remains a challenge mainly because of the complexity and rarity of the disease. Thus, our purposes were to promote a better knowledge of the disease in Emilia-Romagna region (ERR) by creating an accurate and dedicated network; to establish the minimal prevalence of MNGIE in Italy starting from ERR. Blood TP activity level was used as screening test to direct candidates to complete diagnostic work-up. During the study period of 1 year, only 10/71 units of ERR recruited 14 candidates. Their screening did not show TP activity changes. An Italian patient not resident in ERR was actually proved to have MNGIE. At the end of study in Italy there were nine cases of MNGIE; thus, the Italian prevalence of the disease is ~0.15/1,000,000 as a gross estimation. Our study confirms that MNGIE diagnosis is a difficult process which reflects the rarity of the disease and, as a result, a low level of awareness among specialists and physicians. Having available novel therapeutic options (e.g., allogenic hematopoietic stem cell transplantation and, more recently, liver transplantation) and an easy screening test, an early diagnosis should be sought before tissue damage occurs irreversibly. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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128. Microvascular alterations in idiopathic forms of Chronic Intestinal Pseudo- Obstruction: a morphometric and molecular analysis.
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Neri, Irene, Boschetti, Elisa, Caporali, Leonardo, D’Angelo, Roberto, Rinaldi, Rita, Carelli, Valerio, De Giorgio, Roberto, Ratti, Stefano, Cocco, Lucio I. M., and Manzoli, Lucia
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BOWEL obstructions ,MUSCULAR atrophy ,GENETIC disorders ,PROTEIN expression ,BLOOD vessels ,SUBMUCOUS plexus ,JEJUNUM - Abstract
Introduction: Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome characterized by severe gastrointestinal (GI) dysmotility that mimics a GI obstruction in the absence of any mechanical cause CIPO is due to muscular-neuronal-glial-interstitial cells of Cajal abnormalities ¹ and can be idiopathic or secondary to a genetic cause Recently we documented that changes in the microvasculature supplying the gut contribute to GI abnormalities in a genetically driven form of CIPO2 Aim: The object of this study was to investigate if jejunal microvasculature alterations may occur and contribute to the disease also in idiopathic forms of CIPO. Methods: Full thickness jejunal biopsies were collected from n=23 CIPO and n=10 controls. Formalin fixed-paraffin embedded tissue sections were 1) stained with orcein to identify, meas- ure and count blood vessels, that were subdivided in >300μm (large), 300-101μm (medium), 100-51μm (small) and <50μm (very small), 2) stained with Sirius Red/Fast Green- collagen- assay to measure longitudinal muscle layer thickness and to spectrophotometrically determine fibrosis. Frozen tissue was used to assess by western blot Thymidine Phosphorylase (TP) protein expression, as this enzyme is involved in physio-pathological angiogenesis and was found absent in the previously documented form of CIPO secondary to a genetic disorder ² ; and the expression of HIF-1α as marker of hypoxia. Results: CIPO patients showed a lower vascular area with more vessels/mm² submucosa vs. controls. Vessels <50 μm increased at the expense of medium and large vessels. As com- pared to controls, CIPO showed, a higher fi brosis index, hypoxia, a decreased thickness of the longitudinal muscle layer and a decreased number of myenteric neurons. Finally, TP enzyme expression was found decreased in the jejunum of CIPO patients. Conclusion: Our results indicate that the jejunum of CIPO patients is characterized by quantitative and qualitative vascular changes, muscular and neuronal atrophy, fibrosis and hypoxia. Thus, this study allows us to hypothesize that abnormal GI vascularization might be a possible mechanism underlying gut dysfunction in CIPO. [ABSTRACT FROM AUTHOR]
- Published
- 2022
129. Laser micro-anatomical dissection reveals the recovery of mtDNA depletion in the ileum of a Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) patient receiving liver transplant.
- Author
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Boschetti, Elisa, Neri, Irene, Caporali, Leonardo, D’Angelo, Roberto, Rinaldi, Rita, Carelli, Valerio, Giorgio, Roberto De, Ratti, Stefano, Cocco, Lucio I., and Manzoli, Lucia
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MITOCHONDRIAL DNA ,LIVER transplantation ,MITOCHONDRIA ,ILEUM ,NEMALINE myopathy - Abstract
The article presents a study on recovery of mtDNA depletion in the ileum of a Mitochondrial Nero-Gastrointestinal Encephalomyopathy (MNGIE) patient receiving liver transplant. Topics include information on mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); gene encoding for thymidine phosphorylase (TP); and imbalance of mitochondrial nucleotide pool impaired mtDNA replication and depletion.
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- 2022
130. Author Correction: Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.
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La Morgia, Chiara, Maresca, Alessandra, Amore, Giulia, Gramegna, Laura Ludovica, Carbonelli, Michele, Scimonelli, Emanuela, Danese, Alberto, Patergnani, Simone, Caporali, Leonardo, Tagliavini, Francesca, Del Dotto, Valentina, Capristo, Mariantonietta, Sadun, Federico, Barboni, Piero, Savini, Giacomo, Evangelisti, Stefania, Bianchini, Claudio, Valentino, Maria Lucia, Liguori, Rocco, and Tonon, Caterina
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CALCIUM ions ,MITOCHONDRIAL pathology ,WOLFRAM syndrome - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]
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- 2020
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131. REVISITING THE ISSUE OF MITOCHONDRIAL DNA CONTENT IN OPTIC MITOCHONDRIOPATHIES.
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Iommarini, Luisa, Maresca, Alessandra, Caporali, Leonardo, Valentino, Maria Lucia, Liguori, Rocco, Giordano, Carla, and Carelli, Valerio
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- 2012
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132. A computational study to assess the pathogenicity of single or combinations of missense variants on respiratory complex I.
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Rigobello, Laura, Lugli, Francesca, Caporali, Leonardo, Bartocci, Alessio, Fadanni, Jacopo, Zerbetto, Francesco, Iommarini, Luisa, Carelli, Valerio, Ghelli, Anna Maria, and Musiani, Francesco
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MISSENSE mutation , *MITOCHONDRIAL DNA , *ENZYME kinetics , *MOLECULAR dynamics , *OXIDATIVE phosphorylation , *GENETIC disorders - Abstract
Variants found in the respiratory complex I (CI) subunit genes encoded by mitochondrial DNA can cause severe genetic diseases. However, it is difficult to establish a priori whether a single or a combination of CI variants may impact oxidative phosphorylation. Here we propose a computational approach based on coarse-grained molecular dynamics simulations aimed at investigating new CI variants. One of the primary CI variants associated with the Leber hereditary optic neuropathy (m.14484T>C/ MT-ND6) was used as a test case and was investigated alone or in combination with two additional rare CI variants whose role remains uncertain. We found that the primary variant positioned in the E-channel region, which is fundamental for CI function, stiffens the enzyme dynamics. Moreover, a new mechanism for the transition between π- and α-conformation in the helix carrying the primary variant is proposed. This may have implications for the E-channel opening/closing mechanism. Finally, our findings show that one of the rare variants, located next to the primary one, further worsens the stiffening, while the other rare variant does not affect CI function. This approach may be extended to other variants candidate to exert a pathogenic impact on CI dynamics, or to investigate the interaction of multiple variants. • CI variants found in mtDNA encoded subunit genes can cause severe genetic diseases. • Here we propose a CG MD approach aimed at the study of new CI variants. • We successfully applied our approach on three LHON variants. • The primary m.14484 T > C/ MT-ND6 variant stiffens CI dynamics in the E-channel region. • One of the other variants further worsens the stiffening of CI dynamics. [ABSTRACT FROM AUTHOR]
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- 2024
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133. Ultrastruttura e Citochimica Dell'Apparato Austoriale DellaPlasmopara HelianthiNovot
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Marte, Mario, primary and Caporali, Leonardo, additional
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- 1976
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134. Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts.
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Boso, Daniele, Tognon, Martina, Curtarello, Matteo, Minuzzo, Sonia, Piga, Ilaria, Brillo, Valentina, Lazzarini, Elisabetta, Carlet, Jessica, Marra, Ludovica, Trento, Chiara, Rasola, Andrea, Masgras, Ionica, Caporali, Leonardo, Del Ben, Fabio, Brisotto, Giulia, Turetta, Matteo, Pastorelli, Roberta, Brunelli, Laura, Navaglia, Filippo, and Esposito, Giovanni
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WARBURG Effect (Oncology) , *MOLECULAR cloning , *OVARIAN cancer , *CLONE cells , *GLUCOSE , *VASCULAR endothelial growth factor antagonists , *XENOGRAFTS - Abstract
Background: Genetic and metabolic heterogeneity are well-known features of cancer and tumors can be viewed as an evolving mix of subclonal populations, subjected to selection driven by microenvironmental pressures or drug treatment. In previous studies, anti-VEGF therapy was found to elicit rewiring of tumor metabolism, causing marked alterations in glucose, lactate ad ATP levels in tumors. The aim of this study was to evaluate whether differences in the sensitivity to glucose starvation existed at the clonal level in ovarian cancer cells and to investigate the effects induced by anti-VEGF therapy on this phenotype by multi-omics analysis. Methods: Clonal populations, obtained from both ovarian cancer cell lines (IGROV-1 and SKOV3) and tumor xenografts upon glucose deprivation, were defined as glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones based on their in vitro behaviour. GDR and GDS clones were characterized using a multi-omics approach, including genetic, transcriptomic and metabolic analysis, and tested for their tumorigenic potential and reaction to anti-angiogenic therapy. Results: Two clonal populations, GDR and GDS, with strikingly different viability following in vitro glucose starvation, were identified in ovarian cancer cell lines. GDR clones survived and overcame glucose starvation-induced stress by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and both pyruvate and lipids uptake, whereas GDS clones were less able to adapt and died. Treatment of ovarian cancer xenografts with the anti-VEGF drug bevacizumab positively selected for GDR clones that disclosed increased tumorigenic properties in NOD/SCID mice. Remarkably, GDR clones were more sensitive than GDS clones to the mitochondrial respiratory chain complex I inhibitor metformin, thus suggesting a potential therapeutic strategy to target the OXPHOS-metabolic dependency of this subpopulation. Conclusion: A glucose-deprivation resistant population of ovarian cancer cells showing druggable OXPHOS-dependent metabolic traits is enriched in experimental tumors treated by anti-VEGF therapy. [ABSTRACT FROM AUTHOR]
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- 2023
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135. Co-occurrence of amyotrophic lateral sclerosis and Leber's hereditary optic neuropathy: is mitochondrial dysfunction a modifier?
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Amore, Giulia, Vacchiano, Veria, La Morgia, Chiara, Valentino, Maria L., Caporali, Leonardo, Fiorini, Claudio, Ormanbekova, Danara, Salvi, Fabrizio, Bartoletti-Stella, Anna, Capellari, Sabina, Liguori, Rocco, and Carelli, Valerio
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AMYOTROPHIC lateral sclerosis , *LEBER'S hereditary optic atrophy , *MITOCHONDRIAL pathology , *MITOCHONDRIA , *NEUROPATHY - Abstract
Dear Sirs, Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing selective loss of motor neurons in brain motor cortex and spinal cord in which muscle denervation and atrophy are associated with pyramidal involvement, typically spreading to contiguous muscular regions and leading eventually to a fatal paralysis. Here, we report two ALS cases carrying the m.11778A > G/ I MT-ND4 i (R340H) mitochondrial DNA (mtDNA) mutation pathogenic for Leber's hereditary optic neuropathy (LHON), a maternally inherited disease due to mtDNA mutations affecting complex I function and usually leading to isolated optic atrophy [[2]]. Pathogenic mtDNA mutations have been found in ALS phenocopies with a primary mitochondrial disorder [[12]] and, more recently, mutations in nuclear genes, such as I CHCHD10 i , have been associated with ALS and mitochondrial myopathy with accumulation of mtDNA multiple deletions [[13]]. [Extracted from the article]
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- 2023
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136. Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys.
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Capristo, Mariantonietta, Del Dotto, Valentina, Tropeano, Concetta Valentina, Fiorini, Claudio, Caporali, Leonardo, La Morgia, Chiara, Valentino, Maria Lucia, Montopoli, Monica, Carelli, Valerio, and Maresca, Alessandra
- Abstract
Background: Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNALys gene at position m.8344A > G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements. Methods: We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment. Results: The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB). Conclusions: Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF. [ABSTRACT FROM AUTHOR]
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- 2022
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137. Modelling MERRF in 3D cortical organoids: manipulating patient-derived iPSCs to gain insight on prospective pre-clinical therapeutic strategies.
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Capirossi, Giada, Capristo, Mariantonietta, Sacchetti, Giulia, Del Dotto, Valentina, Fiorini, Claudio, Caporali, Leonardo, La Morgia, Chiara, Pisano, Annalinda, Giordano, Carla, D'Amati, Giulia, Le, Stephanie, Prigione, Alessandro, Carelli, Valerio, and Maresca, Alessandra
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ORGANOIDS - Published
- 2024
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138. Genetic variants of NQO1 affect the expression and activity of the protein, which determines the efficacy of idebenone treatment in Leber's hereditary optic neuropathy.
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Del Dotto, Valentina, Aleo, Serena J., Romagnoli, Martina, Fiorini, Claudio, Capirossi, Giada, Peron, Camille, Fasano, Chiara, Maresca, Alessandra, Caporali, Leonardo, Capristo, Mariantonietta, Tropeano, Concetta V., Zanna, Claudia, Porcelli, Anna M., Tioli, Gaia, Amore, Giulia, La Morgia, Chiara, Tiranti, Valeria, Carelli, Valerio, and Ghelli, Anna
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GENETIC variation , *PROTEIN expression , *NEUROPATHY - Published
- 2024
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- View/download PDF
139. Rapamycin rescues mitochondrial dysfunction in cells carrying the m.8344A > G mutation in the mitochondrial tRNALys.
- Author
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Capristo, Mariantonietta, Del Dotto, Valentina, Tropeano, Concetta Valentina, Fiorini, Claudio, Caporali, Leonardo, La Morgia, Chiara, Valentino, Maria Lucia, Montopoli, Monica, Carelli, Valerio, and Maresca, Alessandra
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MITOCHONDRIAL DNA , *TRANSFER RNA , *MITOCHONDRIA , *RAPAMYCIN , *NIACIN , *MITOCHONDRIAL proteins , *MUSCLE weakness - Abstract
Background: Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNALys gene at position m.8344A > G. Defective tRNALys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements. Methods: We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD+ precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment. Results: The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB). Conclusions: Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
140. The relevance of migraine in the clinical spectrum of mitochondrial disorders.
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Terrin, Alberto, Bello, Luca, Valentino, Maria Lucia, Caporali, Leonardo, Sorarù, Gianni, Carelli, Valerio, Maggioni, Ferdinando, Zeviani, Massimo, and Pegoraro, Elena
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MITOCHONDRIAL pathology , *MIGRAINE , *NUCLEAR magnetic resonance spectroscopy , *NEUROMUSCULAR transmission , *CYTOPLASMIC inheritance , *DISABILITIES - Abstract
Recent scientific evidence suggests a link between migraine and brain energy metabolism. In fact, migraine is frequently observed in mitochondrial disorders. We studied 46 patients affected by mitochondrial disorders, through a headache-focused semi-structured interview, to evaluate the prevalence of migraine among patients affected by mitochondrial disorders, the possible correlations between migraine and neuromuscular genotype or phenotype, comorbidities, lactate acid levels and brain magnetic resonance spectroscopy. We explored migraine-related disability, analgesic and prophylactic treatments. Diagnoses were achieved according to International Classification of Headache Disorders, 3rd edition. Lifetime prevalence of migraine was 61% (28/46), with high values in both sexes (68% in females, 52% in males) and higher than the values found in both the general population and previous literature. A maternal inheritance pattern was reported in 57% of cases. MIDAS and HIT6 scores revealed a mild migraine-related disability. The high prevalence of migraine across different neuromuscular phenotypes and genotypes suggests that migraine itself may be a common clinical manifestation of brain energy dysfunction. Our results provide new relevant indications in favour of migraine as the result of brain energy unbalance. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
141. Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.
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La Morgia, Chiara, Maresca, Alessandra, Amore, Giulia, Gramegna, Laura Ludovica, Carbonelli, Michele, Scimonelli, Emanuela, Danese, Alberto, Patergnani, Simone, Caporali, Leonardo, Tagliavini, Francesca, Del Dotto, Valentina, Capristo, Mariantonietta, Sadun, Federico, Barboni, Piero, Savini, Giacomo, Evangelisti, Stefania, Bianchini, Claudio, Valentino, Maria Lucia, Liguori, Rocco, and Tonon, Caterina
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CALCIUM , *MITOCHONDRIAL pathology , *OPTICAL coherence tomography , *ENDOPLASMIC reticulum , *WOLFRAMITE - Abstract
Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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142. SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.
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Del Dotto, Valentina, Ullah, Farid, Di Meo, Ivano, Magini, Pamela, Gusic, Mirjana, Maresca, Alessandra, Caporali, Leonardo, Palombo, Flavia, Tagliavini, Francesca, Baugh, Evan Harris, Macao, Bertil, Szilagyi, Zsolt, Peron, Camille, Gustafson, Margaret A., Khan, Kamal, La Morgia, Chiara, Barboni, Piero, Carbonelli, Michele, Valentino, Maria Lucia, and Liguori, Rocco
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MITOCHONDRIAL DNA , *LEBER'S hereditary optic atrophy , *KIDNEY failure , *CYTOCHROME c , *ATROPHY , *SINGLE-stranded DNA - Abstract
Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
143. New insights into idebenone therapy in relation to NQO1.
- Author
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La Morgia, Chiara, Aleo, Serena Jasmine, Del Dotto, Valentina, Romagnoli, Martina, Fiorini, Claudio, Capirossi, Giada, Peron, Camille, Maresca, Alessandra, Caporali, Leonardo, Capristo, Mariantonietta, Tropeano, Concetta Valentina, Zanna, Claudia, Ross‐Cisneros, Fred, Sadun, Alfredo A., Pignataro, Maria Gemma, Giordano, Carla, Fasano, Chiara, Porcelli, Anna Maria, Tioli, Gaia, and Musiani, Francesco
- Subjects
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GENETIC variation , *MITOCHONDRIAL DNA , *VISION , *TREATMENT effectiveness , *CELL physiology - Abstract
Idebenone is the only approved treatment for Leber's hereditary optic neuropathy (LHON). It promotes recovery of visual function in up to 50% of patients, but, based on the current knowledge, we can neither predict nor understand the non‐responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We explored the possibility that genetic variant in the NQO1 enzyme can impact on idebenone response. We found that two polymorphic variants drastically reduce NQO1 protein levels, when homozygous or in compound heterozygote combination affecting idebenone reduction. In its oxidized form idebenone inhibits complex I, decreasing respiratory function in cells. We also retrospectively analysed a large cohort of LHON treated patients, classified by their response to therapy, demonstrating that patients homozygous or compound heterozygote for the NQO1 variants are characterized by the worst therapy response, particularly if carrying the m.3460G>A/MT‐ND1 LHON mutation. In summary, these results support the concept that the response to idebenone therapy may be influenced by the NQO1 genotype and the different mitochondrial DNA mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
144. The Pattern of Retinal Ganglion Cell Loss in Wolfram Syndrome is Distinct From Mitochondrial Optic Neuropathies
- Author
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Piero Barboni, Giulia Amore, Maria Lucia Cascavilla, Marco Battista, Giulio Frontino, Martina Romagnoli, Leonardo Caporali, Cristina Baldoli, Laura Ludovica Gramegna, Elisa Sessagesimi, Riccardo Bonfanti, Andrea Romagnoli, Roberta Scotti, Maria Brambati, Michele Carbonelli, Vincenzo Starace, Claudio Fiorini, Roberta Panebianco, Vincenzo Parisi, Caterina Tonon, Francesco Bandello, Valerio Carelli, Chiara La Morgia, Barboni, Piero, Amore, Giulia, Cascavilla, Maria Lucia, Battista, Marco, Frontino, Giulio, Romagnoli, Martina, Caporali, Leonardo, Baldoli, Cristina, Gramegna, Laura Ludovica, Sessagesimi, Elisa, Bonfanti, Riccardo, Romagnoli, Andrea, Scotti, Roberta, Brambati, Maria, Carbonelli, Michele, Starace, Vincenzo, Fiorini, Claudio, Panebianco, Roberta, Parisi, Vincenzo, Tonon, Caterina, Bandello, Francesco, Carelli, Valerio, and La Morgia, Chiara
- Subjects
Cohort Studies ,Retinal Ganglion Cells ,Ophthalmology ,Optic Atrophy, Autosomal Dominant ,Optic Nerve Diseases ,Vision Disorders ,Humans ,Wolfram Syndrome ,Tomography, Optical Coherence ,Mitochondria ,Retrospective Studies - Abstract
PURPOSE: To describe the clinical phenotype of a cohort of patients with Wolfram syndrome (WS), focusing on the pattern of optic atrophy correlated with brain magnetic resonance imaging (MRI) measurements, as compared with patients with OPA1-related dominant optic atrophy (DOA).center dot DESIGN: Retrospective, comparative cohort study.center dot METHODS: We reviewed 25 patients with WS and 33 age-matched patients affected by OPA1-related DOA. Ophthalmologic, neurologic, endocrinologic, and MRI data from patients with WS were retrospectively retrieved. Ophthalmologic data were compared with data from patients with OPA1-related DOA and further analyzed for age dependency dividing patients in age quartiles. In a subgroup of patients with WS, we correlated the structural damage assessed by optical coherence tomography (OCT) with brain MRI morphologic measurements. Visual acuity (VA), visual field mean defect (MD), retinal nerve fiber layer (RNFL), and ganglion cell layer (GCL) thickness were assessed by OCT and MRI morphologic measurements of anterior and posterior visual pathways.center dot RESULTS: Optic atrophy was present in 100% of patients with WS. VA, MD, and RNFL thickness loss were worse in patients with WS with a faster decline since early age as compared with patients with DOA, who displayed a more stable visual function over the years. Conversely, GCL sectors were overall thinner in patients with DOA since early age compared to patients with WS, in which GCL thickness started to decline later in life. The neuroradiologic subanalysis on 11 patients with WS exhibited bilateral thinning of the anterior optic pathway, especially the prechiasmatic optic nerves and optic tracts. Optic tract thinning was significantly correlated with GCL thickness but not with RNFL parameters.center dot CONCLUSIONS: Our results showed a generally more severe and diffuse degeneration of both anterior and posterior visual pathways in patients with WS, with fast deterioration of visual function and structural OCT parameters since early age. The pattern observed with OCT suggests that retinal ganglion cell axonal degeneration (ie, RNFL) precedes cellular body atrophy (ie, GCL) by about a decade. This differs substantially from DOA, in which a more stable visual function is evident with predominant early loss of GCL, indirectly supporting the lack of a primary mitochondrial dysfunction in patients with WS. (Am J Ophthalmol 2022;241: 206-216. (c) 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
145. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion
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Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J Siira, Louise Jenninger, Aleksandra Filipovska, Anders R Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson, Misic, Jelena, Milenkovic, Dusanka, Al-Behadili, Ali, Xie, Xie, Jiang, Min, Jiang, Shan, Filograna, Roberta, Koolmeister, Camilla, Siira, Stefan J, Jenninger, Louise, Filipovska, Aleksandra, Clausen, Anders R, Caporali, Leonardo, Valentino, Maria Lucia, La Morgia, Chiara, Carelli, Valerio, Nicholls, Thomas J, Wredenberg, Anna, Falkenberg, Maria, and Larsson, Nils-Göran
- Subjects
Mammals ,DNA Replication ,Mice ,Animal ,Ribonuclease H ,Genetics ,Animals ,RNA ,DNA, Mitochondrial ,Mammal ,Mitochondria - Abstract
The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.
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- 2022
146. Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors
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Manuel Sobrinho-Simões, Silke Haim, Leonardo Caporali, Monica De Luise, Oleksiy Tsybrovskyy, Dario de Biase, Giuseppe Gasparre, Valerio Carelli, Dominik Hackl, Claudio Fiorini, Giovanni Tallini, Larisa Imamovic, Tsybrovskyy, Oleksiy, De Luise, Monica, Biase, Dario, Caporali, Leonardo, Fiorini, Claudio, Gasparre, Giuseppe, Carelli, Valerio, Hackl, Dominik, Imamovic, Larisa, Haim, Silke, Sobrinho‐Simões, Manuel, and Tallini, Giovanni
- Subjects
Mitochondrial DNA ,endocrine system diseases ,tall cell variant papillary carcinoma ,oncocytic tumor ,oncocytic tumors ,Biology ,Mitochondrion ,medicine.disease_cause ,DNA, Mitochondrial ,Oxidative Phosphorylation ,Pathology and Forensic Medicine ,Thyroid carcinoma ,medicine ,Pathology ,Humans ,RB1-214 ,Thyroid Neoplasms ,Prohibitin ,mitochondrial DNA mutations ,thyroid tumor diagnosis ,Mutation ,BRAF V600E ,NDUFS4 ,Molecular biology ,Carcinoma, Papillary ,Heteroplasmy ,mitochondria ,mitochondrial DNA mutation ,Thyroid Cancer, Papillary ,papillary thyroid carcinoma ,Neoplastic cell - Abstract
Papillary thyroid carcinoma tall cell variant (PTC-TCV), a form of PTC regarded as an aggressive subtype, shares several morphologic features with oncocytic tumors. Pathogenic homoplasmic/highly heteroplasmic somatic mitochondrial DNA (mtDNA) mutations, usually affecting oxidative phosphorylation (OXPHOS) complex I subunits, are hallmarks of oncocytic cells. To clarify the relationship between PTC-TCV and oncocytic thyroid tumors, 17 PTC-TCV and 16 PTC non-TCV controls (cPTC) were subjected to: (1) transmission electron microscopy (TEM) to assess mitochondria accumulation, (2) next-generation sequencing to analyze mtDNA and nuclear genes frequently mutated in thyroid carcinoma, and (3) immunohistochemistry (IHC) for prohibitin and complex I subunit NDUFS4 to evaluate OXPHOS integrity. TEM showed replacement of cytoplasm by mitochondria in PTC-TCV but not in cPTC cells. All 17 PTC-TCV had at least one mtDNA mutation, totaling 21 mutations; 3/16 cPTC (19%) had mtDNA mutations (p < 0.001). PTC-TCV mtDNA mutations were homoplasmic/highly heteroplasmic, 16/21 (76%) mapping within mtDNA-encoded complex I subunits. MtDNA mutations in cPTC were homoplasmic in 2 cases and at low heteroplasmy in the third case, 2/3 mapping to mtDNA-encoded complex I subunits; 2/3 cPTC with mtDNA mutations had small tall cell subpopulations. PTC-TCV showed strong prohibitin expression and cPTC low-level expression, consistent with massive and limited mitochondrial content, respectively. All 17 PTC-TCV showed NDUFS4 loss (partial or complete) and 3 of 16 cPTC (19%) had (partial) NDUFS4 loss, consistent with lack of complex I integrity in PTC-TCV (p < 0.001). IHC loss of NDUFS4 was associated with mtDNA mutations (p < 0.001). Four BRAF V600E mutated PTCs had loss of NDUSF4 expression limited to neoplastic cell subpopulations with tall cell features, indicating that PTCs first acquire BRAF V600E and then mtDNA mutations. Similar to oncocytic thyroid tumors, PTC-TCV is characterized by mtDNA mutations, massive accumulation of mitochondria, and loss of OXPHOS integrity. IHC loss of NDUFS-4 can be used as a surrogate marker for OXPHOS disruption and to reliably diagnose PTC-TCV.
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- 2022
147. Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models.
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Del Dotto, Valentina, La Morgia, Chiara, Carelli, Valerio, Fogazza, Mario, Musiani, Francesco, Aleo, Serena J., Rugolo, Michela, Zanna, Claudia, Maresca, Alessandra, Caporali, Leonardo, Nolli, Cecilia, Lodi, Tiziana, Goffrini, Paola, Baruffini, Enrico, and Chan, David
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MICROBIAL virulence , *FIBROBLASTS , *PATHOLOGICAL physiology , *MITOCHONDRIAL DNA , *YEAST - Abstract
OPA1 is the major gene responsible for Dominant Optic Atrophy (DOA) and the syndromic form DOA “plus”. Over 370 OPA1 mutations have been identified so far, although their pathogenicity is not always clear. We have analyzed one novel and a set of known OPA1 mutations to investigate their impact on protein functions in primary skin fibroblasts and in two “ad hoc” generated cell systems: the MGM1/OPA1 chimera yeast model and the Opa1 −/− MEFs model expressing the mutated human OPA1 isoform 1. The yeast model allowed us to confirm the deleterious effects of these mutations and to gain information on their dominance/recessivity. The MEFs model enhanced the phenotypic alteration caused by mutations, nicely correlating with the clinical severity observed in patients, and suggested that the DOA “plus” phenotype could be induced by the combinatorial effect of mitochondrial network fragmentation with variable degrees of mtDNA depletion. Overall, the two models proved to be valuable tools to functionally assess and define the deleterious mechanism and the pathogenicity of novel OPA1 mutations, and useful to testing new therapeutic interventions. [ABSTRACT FROM AUTHOR]
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- 2018
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148. Brain MRS correlates with mitochondrial dysfunction biomarkers in MELAS‐associated mtDNA mutations
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Lidia Di Vito, Lia Talozzi, Caterina Tonon, Maria Lucia Valentino, Stefania Evangelisti, Rocco Liguori, Giulia Amore, David Neil Manners, Irene Cortesi, Valerio Carelli, Claudia Testa, Chiara La Morgia, Claudio Bianchini, Alessandra Maresca, Laura Ludovica Gramegna, Raffaele Lodi, Leonardo Caporali, Gramegna, Laura L, Evangelisti, Stefania, Di Vito, Lidia, La Morgia, Chiara, Maresca, Alessandra, Caporali, Leonardo, Amore, Giulia, Talozzi, Lia, Bianchini, Claudio, Testa, Claudia, Manners, David N, Cortesi, Irene, Valentino, Maria L, Liguori, Rocco, Carelli, Valerio, Tonon, Caterina, and Lodi, Raffaele
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Male ,0301 basic medicine ,Mitochondrial encephalomyopathy ,Proton Magnetic Resonance Spectroscopy ,Choline ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebellum ,Lateral Ventricles ,MELAS Syndrome ,Research Articles ,Cerebral Cortex ,General Neuroscience ,Neurodegeneration ,Middle Aged ,White Matter ,Heteroplasmy ,medicine.anatomical_structure ,Lactic acidosis ,MELAS ,1 H-MRS ,brain proton magnetic resonance spectroscopy ,Research Article ,RC321-571 ,Adult ,medicine.medical_specialty ,Mitochondrial DNA ,Adolescent ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Creatine ,DNA, Mitochondrial ,White matter ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,MELAS-Spectrum Syndrome ,RC346-429 ,Aged ,Aspartic Acid ,business.industry ,mtDNA mutation ,medicine.disease ,030104 developmental biology ,Endocrinology ,chemistry ,Mutation ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,business ,Biomarkers ,Inositol ,030217 neurology & neurosurgery - Abstract
Objective The purpose of this study was to investigate correlations between brain proton magnetic resonance spectroscopy (1H‐MRS) findings with serum biomarkers and heteroplasmy of mitochondrial DNA (mtDNA) mutations. This study enrolled patients carrying mtDNA mutations associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke‐like episodes (MELAS), and MELAS‐Spectrum Syndrome (MSS). Methods Consecutive patients carrying mtDNA mutations associated with MELAS and MSS were recruited and their serum concentrations of lactate, alanine, and heteroplasmic mtDNA mutant load were evaluated. The brain protocol included single‐voxel 1H‐MRS (1.5T) in the medial parieto‐occipital cortex (MPOC), left cerebellar hemisphere, parieto‐occipital white matter (POWM), and lateral ventricles. Relative metabolite concentrations of N‐acetyl‐aspartate (NAA), choline (Cho), and myo‐inositol (mI) were estimated relative to creatine (Cr), using LCModel 6.3. Results Six patients with MELAS (age 28 ± 13 years, 3 [50%] female) and 17 with MSS (age 45 ± 11 years, 7 [41%] female) and 39 sex‐ and age‐matched healthy controls (HC) were enrolled. These patients demonstrated a lower NAA/Cr ratio in MPOC compared to HC (p = 0.006), which inversely correlated with serum lactate (p = 0.021, rho = −0.68) and muscle mtDNA heteroplasmy (p
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- 2021
149. Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder
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Leonardo Caporali, Claudio Fiorini, Flavia Palombo, Martina Romagnoli, Flavia Baccari, Corrado Zenesini, Paola Visconti, Annio Posar, Maria Cristina Scaduto, Danara Ormanbekova, Agatino Battaglia, Raffaella Tancredi, Cinzia Cameli, Marta Viggiano, Anna Olivieri, Antonio Torroni, Elena Maestrini, Magali Jane Rochat, Elena Bacchelli, Valerio Carelli, Alessandra Maresca, Caporali, Leonardo, Fiorini, Claudio, Palombo, Flavia, Romagnoli, Martina, Baccari, Flavia, Zenesini, Corrado, Visconti, Paola, Posar, Annio, Scaduto, Maria Cristina, Ormanbekova, Danara, Battaglia, Agatino, Tancredi, Raffaella, Cameli, Cinzia, Viggiano, Marta, Olivieri, Anna, Torroni, Antonio, Maestrini, Elena, Rochat, Magali Jane, Bacchelli, Elena, Carelli, Valerio, and Maresca, Alessandra
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Genetics ,Molecular Medicine ,mitochondrial DNA, mitochondrial haplogroups, universal heteroplasmy, autism spectrum disorder, autism risk ,Genetics (clinical) - Abstract
Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%–5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers’ germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.
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- 2022
150. Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions
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Arianna Manini, Leonardo Caporali, Megi Meneri, Simona Zanotti, Daniela Piga, Ignazio Giuseppe Arena, Stefania Corti, Antonio Toscano, Giacomo Pietro Comi, Olimpia Musumeci, Valerio Carelli, Dario Ronchi, Manini, Arianna, Caporali, Leonardo, Meneri, Megi, Zanotti, Simona, Piga, Daniela, Arena, Ignazio Giuseppe, Corti, Stefania, Toscano, Antonio, Comi, Giacomo Pietro, Musumeci, Olimpia, Carelli, Valerio, and Ronchi, Dario
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CPEO ,RNASEH1 ,Genetics ,Molecular Medicine ,mtDNA maintenance disorder ,ribonuclease H1 ,mitochondrial DNA ,Genetics (clinical) ,myopathy - Abstract
Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis.
- Published
- 2022
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