Epithelial NAD + depletion drives mitochondrial dysfunction and contributes to intestinal inflammation.

Autor:	Novak EA; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Crawford EC; Division of Gastroenterology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Mentrup HL; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Griffith BD; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, United States., Fletcher DM; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Flanagan MR; University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Schneider C; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Firek B; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Rogers MB; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Morowitz MJ; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Piganelli JD; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Wang Q; Department of Pathology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Mollen KP; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.; Division of Pediatric General and Thoracic Surgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Sep 07; Vol. 14, pp. 1231700. Date of Electronic Publication: 2023 Sep 07 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1231700
Abstrakt:	Introduction: We have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear. Methods: Mice (male; C57Bl/6, Villincre /+; Pgc1afl/fl mice, and Pgc1afl/fl ) were subjected to experimental colitis and treated with nicotinamide riboside. Western blot, high-resolution respirometry, nicotinamide adenine dinucleotide (NAD+) quantification, and immunoprecipitation were used to in this study. Results: We demonstrate a significant depletion in the NAD+ levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis. While we found no decrease in the levels of NAD+-synthesizing enzymes within the intestinal epithelium of mice undergoing experimental colitis, we did find an increase in the mRNA level, as well as the enzymatic activity, of the NAD+-consuming enzyme poly(ADP-ribose) polymerase-1 (PARP1). Treatment of mice undergoing experimental colitis with an NAD+ precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1α levels; however, NAD+ repletion did not benefit transgenic mice that lack PGC1α within the intestinal epithelium, suggesting that the therapeutic effects require an intact PGC1α axis. Discussion: Our results emphasize the importance of PGC1α expression to both mitochondrial health and homeostasis within the intestinal epithelium and suggest a novel therapeutic approach for disease management. These findings also provide a mechanistic basis for clinical trials of nicotinamide riboside in IBD patients. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Novak, Crawford, Mentrup, Griffith, Fletcher, Flanagan, Schneider, Firek, Rogers, Morowitz, Piganelli, Wang and Mollen.)
Databáze:	MEDLINE
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