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

PLoS One. 2019 Nov 7;14(11):e0224132. doi: 10.1371/journal.pone.0224132. eCollection 2019.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Bees / metabolism
  • Cells, Cultured
  • Drug Resistance, Fungal / drug effects
  • Electron Transport / drug effects*
  • Fungal Proteins / pharmacology
  • Fungi / metabolism
  • Humans
  • Mitochondrial Membranes / drug effects
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Oligochaeta / metabolism
  • Pesticides / pharmacology*
  • Succinate Dehydrogenase / antagonists & inhibitors*
  • Succinate Dehydrogenase / metabolism

Substances

  • Antioxidants
  • Fungal Proteins
  • Pesticides
  • Succinate Dehydrogenase

Grant support

No specific funding was initially provided for this work. After the work realization, PB and PR received a specific support grant from the French Association POLLINIS (https://www.pollinis.org/). General expenses were covered by grants from AAJI (Association pour l'Aide aux Jeunes Infirmes & aux Personnes Handicapées); AFAF (Association Française de l'Ataxie de Friedreich); Association OLY (Ouvrir Les Yeux); ANR MITOXDRUGS (ANR-16-CE18-0010). Sponsors or funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.