title: Combined use of Saccharomyces cerevisiae, Caenorhabditis elegans and patient fibroblasts leads to the identification of clofilium tosylate as a potential therapeutic chemical against POLG-related diseases.
abstract: Mitochondria are organelles that have their own DNA (mitochondrial DNA, mtDNA) whose maintenance is necessary for the majority of ATP production in eukaryotic cells. Defects in mtDNA maintenance or integrity are responsible for numerous diseases. The DNA polymerase γ (POLG) ensures proper mtDNA replication and repair. Mutations in POLG are a major cause of mitochondrial disorders including hepatic insufficiency, Alpers syndrome, progressive external ophthalmoplegia, sensory neuropathy and ataxia. Mutations in POLG are also associated with parkinsonism. To date, no effective therapy is available. Based on the conservation of mitochondrial function from yeast to human, we used Saccharomyces cerevisiae and Caenorhabditis elegans as first pass filters to identify a chemical that suppresses mtDNA instability in cultured fibroblasts of a POLG-deficient patient. We showed that this unsuspected compound, clofilium tosylate (CLO), belonging to a class of anti-arrhythmic agents, prevents mtDNA loss of all yeast mitochondrial polymerase mutants tested, improves behavior and mtDNA content of polg-1-deficient worms and increases mtDNA content of quiescent POLG-deficient fibroblasts. Furthermore, the mode of action of the drug seems conserved as CLO increases POLG steady-state level in yeast and human cells. Two other anti-arrhythmic agents (FDA-approved) sharing common pharmacological properties and chemical structure also show potential benefit for POLG deficiency in C. elegans. Our findings provide evidence of the first mtDNA-stabilizing compound that may be an effective pharmacological alternative for the treatment of POLG-related diseases.
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Laras
authors.initials: L
authors.lastname: Pitayu
authors.affiliation: Department of Life Sciences, University of Parma, Parco Area delle Scienze 11/a, I-43124 Parma, Italy and.
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Rodier
authors.affiliation: INSERM UMR 1163, Laboratory of Genetics of Mitochondrial Disorders, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 24 Boulevard du Montparnasse, Paris 75015, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.affiliation: Department of Life Sciences, University of Parma, Parco Area delle Scienze 11/a, I-43124 Parma, Italy and.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lodi
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France, agnes.delahodde@i2bc.paris-saclay.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Delahodde
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D004256:DNA Polymerase I / Q000235:genetics; D000074002:DNA Polymerase gamma; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D061251:Primary Cell Culture; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D000644:Quaternary Ammonium Compounds; D029701:Saccharomyces cerevisiae Proteins; C022799:clofilium; D004256:DNA Polymerase I; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C068352:MIP1 protein, S cerevisiae; C413027:POLG protein, human