S3QELs protect against diet‐induced intestinal barrier dysfunction

Abstract

The underlying causes of aging remain elusive, but may include decreased intestinal homeostasis followed by disruption of the intestinal barrier, which can be mimicked by nutrient‐rich diets. S3QELs are small‐molecule suppressors of site IIIQo electron leak; they suppress superoxide generation at complex III of the mitochondrial electron transport chain without inhibiting oxidative phosphorylation. Here we show that feeding different S3QELs to Drosophila on a high‐nutrient diet protects against greater intestinal permeability, greater enterocyte apoptotic cell number, and shorter median lifespan. Hif‐1α knockdown in enterocytes also protects, and blunts any further protection by S3QELs. Feeding S3QELs to mice on a high‐fat diet also protects against the diet‐induced increase in intestinal permeability. Our results demonstrate by inference of S3QEL use that superoxide produced by complex III in enterocytes contributes to diet‐induced intestinal barrier disruption in both flies and mice.

Effects of sugars, fatty acids and amino acids on cytosolic and mitochondrial hydrogen peroxide release from liver cells

“…The same was true in a range of cell lines from disparate species and tissues [ 32 ]. The protective effects of S1QELs against pathologies driven by a lack of superoxide dismutase show that site I Q can be a significant source of superoxide in vivo [ 33 ]; the protective effects of S3QELs against pathological effects of a high-fat diet in the gut show the same for site III Qo [ 34 ].…”

Saturated fatty acids differently affect mitochondrial function and the intestinal epithelial barrier depending on their chain length in the in vitro model of IPEC-J2 enterocytes

“…It has been indeed described that ROS alter epithelial barrier integrity through mechanisms linked with the redistribution of the tight junction proteins occludin (OCLN) and zonula occludens-1 (ZO-1) toward the intracellular compartment, the rearrangement of the actin cytoskeleton ( Rao, 2008 ), or the phosphorylation of OCLN, causing its dissociation from ZO-1 ( Gangwar et al, 2017 ). In contrast, treatment of IEC with antioxidants that target mitochondrial ROS in vitro (MitoTEMPO; mitoquinone) or in vivo (S3QELs) prevents the increase in epithelial permeability induced by the dinitrophenol-induced OXPHOS uncoupling ( Wang et al, 2014 ; Lopes et al, 2018 ) or by high-fat diet consumption ( Watson et al, 2021 ).…”

Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology

“…Moreover, at resting state with low OXPHOS and no insulin release at 3 m M glucose, when overal superoxide formation was ∼2.5 higher, site I Q accounted for 25% and site III Qo for 20%. In Drosophilla and mice, experiments with suppressor of site III Qo electron leak (S3QEL) revealed site III Qo as a cause for diet-induced intestinal barrier disruption (Watson et al, 2021 ).…”