title: A method to identify and validate mitochondrial modulators using mammalian cells and the worm C. elegans.
abstract: Mitochondria are semi-autonomous organelles regulated by a complex network of proteins that are vital for many cellular functions. Because mitochondrial modulators can impact many aspects of cellular homeostasis, their identification and validation has proven challenging. It requires the measurement of multiple parameters in parallel to understand the exact nature of the changes induced by such compounds. We developed a platform of assays scoring for mitochondrial function in two complementary models systems, mammalian cells and C. elegans. We first optimized cell culture conditions and established the mitochondrial signature of 1,200 FDA-approved drugs in liver cells. Using cell-based and C. elegans assays, we further defined the metabolic effects of two pharmacological classes that emerged from our hit list, i.e. imidazoles and statins. We found that these two drug classes affect respiration through different and cholesterol-independent mechanisms in both models. Our screening strategy enabled us to unequivocally identify compounds that have toxic or beneficial effects on mitochondrial activity. Furthermore, the cross-species approach provided novel mechanistic insight and allowed early validation of hits that act on mitochondrial function.
authors.affiliation: 1] Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland [2].
authors.forename: Pénélope A
authors.initials: PA
authors.lastname: Andreux
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Virginija
authors.initials: V
authors.lastname: Jovaisaite
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Mottis
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bichet
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.affiliation: 1] Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland [2] Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000145:classification; D015203:Reproducibility of Results; D019821:Simvastatin / Q000494:pharmacology; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D007211:Indoles; D004364:Pharmaceutical Preparations; D000077340:Fluvastatin; D008148:Lovastatin; D019821:Simvastatin