1. Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish
- Author
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Lisa Locatello, Agnès Delahodde, Chiara Fornetto, Maria B. Rasotto, Massimo M. Santoro, Giovanni Risato, Tiziana Lodi, Francesco Vanzi, Laura Martorano, Andrea Vettori, Luisa Dalla Valle, Rudy Celeghin, Giorgia Beffagna, Natascia Tiso, Claudio Laquatra, Alberto Dinarello, Enrico Baruffini, Giacomo Meneghetti, Raquel Brañas Casas, Francesco Argenton, Andrea Rasola, Nicola Facchinello, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fonctions et dysfonctions de la mitochondrie (FDMITO), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Cancer Research ,Mitochondrial DNA ,Mitochondrial Diseases ,[SDV]Life Sciences [q-bio] ,Mitochondrial disease ,Immunology ,Mutant ,Mitochondrion ,Biology ,Article ,clofilium tosylate ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,zebrafish, POLG, mitochondrial disease ,medicine ,Animals ,mutant ,lcsh:QH573-671 ,Zebrafish ,030304 developmental biology ,Phenocopy ,0303 health sciences ,Disease model ,lcsh:Cytology ,Mutagenesis ,Energy metabolism ,Cell Biology ,zebrafish ,medicine.disease ,biology.organism_classification ,Phenotype ,polg, zebrafish, clofilium tosylate, mitochondria, mutant ,3. Good health ,Cell biology ,Experimental models of disease ,Quaternary Ammonium Compounds ,mitochondria ,Disease Models, Animal ,mitochondrial disease ,POLG ,030217 neurology & neurosurgery - Abstract
The DNA polymerase gamma (Polg) is a nuclear-encoded enzyme involved in DNA replication in animal mitochondria. In humans, mutations in the POLG gene underlie a set of mitochondrial diseases characterized by mitochondrial DNA (mtDNA) depletion or deletion and multiorgan defects, named POLG disorders, for which an effective therapy is still needed. By applying antisense strategies, ENU- and CRISPR/Cas9-based mutagenesis, we have generated embryonic, larval-lethal and adult-viable zebrafish Polg models. Morphological and functional characterizations detected a set of phenotypes remarkably associated to POLG disorders, including cardiac, skeletal muscle, hepatic and gonadal defects, as well as mitochondrial dysfunctions and, notably, a perturbed mitochondria-to-nucleus retrograde signaling (CREB and Hypoxia pathways). Next, taking advantage of preliminary evidence on the candidate molecule Clofilium tosylate (CLO), we tested CLO toxicity and then its efficacy in our zebrafish lines. Interestingly, at well tolerated doses, the CLO drug could successfully rescue mtDNA and Complex I respiratory activity to normal levels, even in mutant phenotypes worsened by treatment with Ethidium Bromide. In addition, the CLO drug could efficiently restore cardio-skeletal parameters and mitochondrial mass back to normal values. Altogether, these evidences point to zebrafish as a valuable vertebrate organism to faithfully phenocopy multiple defects detected in POLG patients. Moreover, this model represents an excellent platform to screen, at the whole-animal level, candidate molecules with therapeutic effects in POLG disorders.
- Published
- 2021