Inhibition of Succinate Dehydrogenase by Pesticides (SDHIs) and Energy Metabolism

Abstract

Succinate dehydrogenase (SDH) is one of the enzymes of the tricarboxylic acid cycle (Krebs cycle) and complex II of the mitochondrial respiratory chain. A class of fungicides (SDHIs) targets the complex II reaction in the SDH. A large number of those in use have been shown to inhibit SDH in other phyla, including humans. This raises questions about possible effects on human health and non-target organisms in the environment. The present document will address metabolic consequences in mammals; it is neither a review on SDH nor is it about the toxicology of SDHIs. Most clinically relevant observations are linked to a severe decrease in SDH activity. Here we shall examine the mechanisms for compensating a loss of SDH activity and their possible weaknesses or adverse consequences. It can be expected that a mild inhibition of SDH will be compensated by the kinetic properties of this enzyme, but this implies a proportionate increase in succinate concentration. This would be relevant for succinate signaling and epigenetics (not reviewed here). With regard to metabolism, exposure of the liver to SDHIs would increase the risk for non-alcoholic fatty liver disease (NAFLD). Higher levels of inhibition may be compensated by modification of metabolic fluxes with net production of succinate. SDHIs are much more soluble in lipids than in water; consequently, a different diet composition between laboratory animals and humans is expected to influence their absorption.

Heterogeneous distribution of mitochondria and succinate dehydrogenase activity in human airway smooth muscle cells

“…Malonate‐mediated competitive inhibition of SDHA in hASM cells as well as siRNA‐mediated SDHB knockdown decreased SDH max which was consistent with the reduction of maximum OCR. These results are also consistent with other reports where SDH metabolism was studied using biochemical methods 2,67‐71 …”

“…These results are also consistent with other reports where SDH metabolism was studied using biochemical methods. 2 , 67 , 68 , 69 , 70 , 71 …”

Transcriptome Analysis of mfs2-Defective Penicillium digitatum Mutant to Reveal Importance of Pdmfs2 in Developing Fungal Prochloraz Resistance

“…According to studies in the past years, more and more evidence has emerged to support comprehensive metabolism backgrounds underlying fungicide resistance. Such backgrounds include various ERG-encoding genes in fungal ergosterol biosynthesis pathways [36,41,42], acetyl-CoA carboxylase (ACCase)-encoding genes in the lipid and fatty acid oxidation path-ways [45][46][47], reactive oxygen species (ROS)-metabolizing enzyme-encoding genes in the cell wall maintenance and oxidative-stress-responsive processes [50,51], mitochondrial respiratory chain protein-encoding genes in the cellular energy metabolisms [53][54][55], ubiquitin-encoding genes in the post-translational modification processes [57][58][59], and protein kinase-encoding genes involved in mitogen-activated signal transductions [55,60,61]. In the present study, RNA-seq analysis revealed that Pdmfs2 knockout led to the down-regulation of genes involved in peroxisome (ko04146) and oxidative phosphorylation (ko00190) at no prochloraz treatment (Tables 1 and 2, and Figures 1 and 2).…”

“…These metabolisms and cellular stimuli processes in response to specific fungicide(s) have been studied, including ergosterol biosynthesis pathways, lipid and fatty acid oxidation pathways, cell wall maintenance, oxidative-stress-responsive processes, carbohydrate and amino acid metabolisms, cellular energy metabolisms, post-translational modification processes, and signal transduction pathways. All these pathways are highly dependent on many stress-responsive genes, including various ERG-encoding genes (such as erg1, erg3, erg11, erg24, erg25 and so on) [36,[40][41][42], acetyl-CoA carboxylase (ACCase)-encoding genes [43][44][45][46][47], reactive oxygen species (ROS)-metabolizing enzyme-encoding genes [48][49][50][51], mitochondrial respiratory chain protein-encoding genes [52][53][54][55], ubiquitin-encoding genes [56][57][58][59], and a series of protein kinase-encoding genes involved in mitogen-activated signal transductions [55,60,61]. As reported, MFS and ABC transporters played multiple roles in the transport of a diverse range of metabolic substrates and intermediates [62,63].…”

The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation

“…In vitro experiments using inhibitors such as nitropropionic acid, an irreversible inhibitor, or malonate, a competitive inhibitor, showed that an adverse effect of more than 30% could be observed in the inhibition of enzyme activity. Future studies are needed to clarify whether prolonged exposure to low doses of SDH inhibitor may be harmful for human and animal health [126].…”