S3QELs protect against diet‐induced intestinal barrier dysfunction. Issue 10 (14th September 2021)

• Record Type: Journal Article
• Authors: Watson, Mark A.; Pattavina, Blaine; Hilsabeck, Tyler A. U.; Lopez‐Dominguez, Jose; Kapahi, Pankaj; Brand, Martin D.
• Is Part Of: Aging cell. Volume 20:Issue 10(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-09-14
• Subjects: aging -- complex III -- diet -- drosophila -- intestine -- intestinal permeability -- leaky gut -- metabolism -- mitochondria -- oxidative stress -- superoxide; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13476
• Languages: English
• ISSNs: 1474-9718

Abstract

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. Abstract : Animals fed a high‐nutrient diet exhibit decreased intestinal integrity over time, which coincides with a decreased lifespan. S3QELs inhibit superoxide production specifically from site IIIQo of complex III in mitochondria. Treatment of animals on a high‐nutrient diet with S3QELs increases intestinal integrity resulting in an increased lifespan potentially by decreasing ER stress and Hif‐1α signaling.