Mitochondrial respiratory chain complex I dysfunction induced by N-methyl carbamate ex vivo can be alleviated with a cell-permeable succinate prodrug

Joanna I. Janowska, Sarah Piel, Nahima Saliba, Claire D. Kim, David H. Jang, Michael Karlsson, Todd J. Kilbaugh, Johannes K. Ehinger

Research output: Contribution to journalArticlepeer-review

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-dependent decrease in mitochondral oxygen consumption linked to respiratory chain 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 (100 μM) decrease in mitochondrial 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.

Original languageEnglish
Article number104794
JournalToxicology in Vitro
Volume65
DOIs
Publication statusPublished - 2020

Subject classification (UKÄ)

  • Neurology
  • Cell and Molecular Biology

Free keywords

  • Carbamates
  • Cell-permeable succinate
  • Methyl isocyanate
  • Mitochondria
  • NSNM
  • Respirometry

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