Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype

Research output: Contribution to journalArticle

Abstract

SUGCT (C7orf10) is a mitochondrial enzyme that synthesizes glutaryl-CoA from glutarate in tryptophan and lysine catabolism, but it has not been studied in vivo. Although mutations in Sugct lead to Glutaric Aciduria Type 3 disease in humans, patients remain largely asymptomatic despite high levels of glutarate in the urine. To study the disease mechanism, we generated SugctKO mice and uncovered imbalanced lipid and acylcarnitine metabolism in kidney in addition to changes in the gut microbiome. After SugctKO mice were treated with antibiotics, metabolites were comparable to WT, indicating that the microbiome affects metabolism in SugctKO mice. SUGCT loss of function contributes to gut microbiota dysbiosis, leading to age-dependent pathological changes in kidney, liver, and adipose tissue. This is associated with an obesity-related phenotype that is accompanied by lipid accumulation in kidney and liver, as well as “crown-like” structures in adipocytes. Furthermore, we show that the SugctKO kidney pathology is accelerated and exacerbated by a high-lysine diet. Our study highlights the importance of non-essential genes with no readily detectable early phenotype, but with substantial contributions to the development of age-related pathologies, which result from an interplay between genetic background, microbiome, and diet in the health of mammals.

Details

Authors
  • Joanna Niska-Blakie
  • Lakshmi Gopinathan
  • Kia Ngee Low
  • Yang Lay Kien
  • Christine M.F. Goh
  • Matias J. Caldez
  • Elisabeth Pfeiffenberger
  • Oliver S. Jones
  • Chee Bing Ong
  • Igor V. Kurochkin
  • Vincenzo Coppola
  • Lino Tessarollo
  • Hyungwon Choi
  • Yoganathan Kanagasundaram
  • Frank Eisenhaber
  • Sebastian Maurer-Stroh
  • Philipp Kaldis
Organisations
External organisations
  • A*Star Institute of Molecular and Cell Biology (IMCB)
  • A*Star, Bioinformatics Institute (BII)
  • National University of Singapore
  • Ohio State University
  • National Cancer Institute at Frederick
  • Nanyang Technological University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • C7orf10, Glutaric aciduria type 3 (GA3), Gut microflora, Lipids, Metabolomics, Obesity, Sugct
Original languageEnglish
JournalCellular and Molecular Life Sciences
Publication statusPublished - 2019 Nov
Publication categoryResearch
Peer-reviewedYes