Janowska 2020 Toxicol In Vitro
| Janowska JI, Piel S, Saliba N, Kim CD, Jang DH, Karlsson M, Kilbaugh TJ, Ehinger JK (2020) Mitochondrial respiratory chain Complex I dysfunction induced by N-methyl carbamate ex vivo can be alleviated with a cell-permeable succinate prodrug carbamate toxicity and treatment. Toxicol In Vitro 65:104794. |
Janowska Joanna I, Piel Sarah, Saliba Nahima, Kim Claire D, Jang David H, Karlsson Michael, Kilbaugh Todd J, Ehinger Johannes K (2020) Toxicol In Vitro
Abstract: Human exposure to carbamates and organophosphates poses a serious threat to society and current pharmacological treatment is solely targeting the compounds' inhibitory effect on acetylcholinesterase. This toxicological pathway, responsible for acute symptom presentation, can be counteracted with currently available therapies such as atropine and oximes. However, there is still significant long-term morbidity and mortality. We propose mitochondrial dysfunction as an additional cellular mechanism of carbamate toxicity and suggest pharmacological targeting of mitochondria to overcome acute metabolic decompensation. Here, we investigated the effects on mitochondrial respiratory function of N-succinimidyl N-methylcarbamate (NSNM), a surrogate for carbamate insecticides ex vivo in human platelets. Characterization of the mitochondrial toxicity of NSNM in platelets revealed a dose depended decrease in oxygen consumption linked to respiratory Complex I while the pathway through Complex II was unaffected. In intact platelets, an increase in lactate production was seen, due to a compensatory shift towards anaerobic metabolism. Treatment with a cell-permeable succinate prodrug restored the NSNM-induced (100β―ΞΌM) decrease in oxygen consumption and normalized lactate production to the level of control. We have demonstrated that carbamate-induced mitochondrial Complex I dysfunction can be alleviated with a mitochondrial targeted countermeasure: a cell-permeable prodrug of the mitochondrial Complex II substrate succinate.
Copyright Β© 2019. Published by Elsevier Ltd. β’ Keywords: Carbamates, Cell-permeable succinate, Methyl isocyanate, Mitochondria, MitoKit-CII, NSNM, Respirometry β’ Bioblast editor: Plangger M β’ O2k-Network Lab: US PA Philadelphia Kilbaugh T, US PA Philadelphia Jang DH, SE Lund Elmer E
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Human
Tissue;cell: Blood cells, Platelet
Preparation: Permeabilized cells, Intact cells
Regulation: Aerobic glycolysis Coupling state: LEAK, ROUTINE, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k
Labels, 2020-02, MitoEAGLE blood cells data, MitoKit-CII, SE, US
