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

Abstract

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).

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

“…SDHC, SDHD, MTCO3, and NDUFV3 were identified as being possible candidates. Succinate dehydrogenase as a key component of the mitochondrial respiratory chain (RC) of all living organisms ( 22 ), SDH mutation frequently occurred in cancer ( 23 – 25 ). SDHC has a higher mutation rate compared with SDHD ( 26 ).…”

Bixafen, a succinate dehydrogenase inhibitor fungicide, causes microcephaly and motor neuron axon defects during development

“…A recent study has questioned the specificity of these SDHIs, including bixafen. It showed that the latest-generation SDHIs sold on the market could inhibit the SDH of several species ranging from earthworms to human cells, evidence that these SDHIs are nonspecific (Bénit et al, 2019). Several epidemiological studies published during the last two decades suggest harmful effects of pesticides on human health (Merhi et al, 2007; Weichenthal et al, 2010).…”

“…These severe brain and spinal cord malformations may also be related to the different metabolic abnormalities reported in SDHI exposed animals (Graillot et al, 2012; Qian et al, 2018; Wu et al, 2018; Yang et al, 2018). A recent work (Bénit et al, 2019) has shown that bixafen also exerts an effect on mitochondrial respiration complex III, suggesting an adverse effect of bixafen on cellular metabolism.…”

“…The complex II targeted by SDHI is not specific to the targeted disease fungi but is also closely similar to that present in all plant and animals species, including humans. SDHI inhibitory action on mitochondrial activity has thus been shown to be effective in various models and human cells (Bénit et al, 2019). Additionally, these latest generation SDHIs have been shown to also inhibit mitochondrial respiration complex III (Bénit et al, 2019), suggesting more critical effects of these new fungicides than those expected.…”

“…SDHI inhibitory action on mitochondrial activity has thus been shown to be effective in various models and human cells (Bénit et al, 2019). Additionally, these latest generation SDHIs have been shown to also inhibit mitochondrial respiration complex III (Bénit et al, 2019), suggesting more critical effects of these new fungicides than those expected. SDH activity has been shown to be irreplaceable in mitochondrial metabolism, and defects in its activity impair the cellular metabolome and functions (Bénit et al, 2014).…”