Journal Article

Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells

Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Chretien, Dominique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou (HEGP), Association OLY (Ouvrir Les Yeux), Rustin, Pierre, AFAF (Association Française de l’Ataxie de Friedreich), Rak, Malgorzata, Kahn, Agathe, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Huc, Laurence, Favier, Judith, Serv

2019

Overview

Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. We first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested, albeit with varying IC50 values, generally in the micromolar range. In addition to SDH, we observed that five of the SDHIs, mostly from the latest generation, inhibit the activity of RC complex III. Finally, we show that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer's disease).

• Publisher: CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: Alzheimer's disease / Animals / Antioxidants / Antioxidants (Nutrients) / Antioxidants - metabolism / Ataxia / Bees - metabolism / Binding sites / Biochemistry / Biochemistry, Molecular Biology / Biology and Life Sciences / Carbon sources / Cell culture / Cell death / Cells, Cultured / Chains / Cytochrome b / Dehydrogenases / Drug Resistance, Fungal - drug effects / Electron transport / Electron Transport - drug effects / Encephalopathy / Enzymes / European honeybee / Fibroblasts / Friedreich's ataxia / Fungal Proteins - pharmacology / Fungi / Fungi - metabolism / Fungicides / Glucose / Glucose metabolism / Glutamine / Glycolysis / Humans / Hypersensitivity / Inhibitors / Life Sciences / Masking / Medicine and Health Sciences / Metabolism / Mitochondria / Mitochondrial Membranes - drug effects / Mutation / Nervous system diseases / Neurodegenerative diseases / Neurodegenerative Diseases - drug therapy / Neurodegenerative Diseases - metabolism / Oligochaeta - metabolism / Organisms / Pesticides / Pesticides - pharmacology / Physical Sciences / Research and Analysis Methods / Respiration / Succinate dehydrogenase / Succinate Dehydrogenase - antagonists & inhibitors / Succinate Dehydrogenase - metabolism / Time dependence / Toxicology / Tumors / Vegetal toxicology and mycotoxicology
• ISBN: 0005326944000