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

Niska-Blakie, Joanna ; Gopinathan, Lakshmi ; Low, Kia Ngee ; Kien, Yang Lay ; Goh, Christine M.F. ; Caldez, Matias J. ; Pfeiffenberger, Elisabeth ; Jones, Oliver S. ; Ong, Chee Bing and Kurochkin, Igor V. , et al. (2019) In Cellular and Molecular Life Sciences
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... (More)

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.

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publication status
published
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keywords
C7orf10, Glutaric aciduria type 3 (GA3), Gut microflora, Lipids, Metabolomics, Obesity, Sugct
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Cellular and Molecular Life Sciences
publisher
Birkhäuser Verlag
external identifiers
  • pmid:31722069
  • scopus:85074986360
ISSN
1420-682X
DOI
10.1007/s00018-019-03359-z
language
English
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yes
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005a2a53-8b9b-488c-9822-a2f219dfae6a
date added to LUP
2019-12-06 10:36:38
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2020-09-16 04:36:20
@article{005a2a53-8b9b-488c-9822-a2f219dfae6a,
  abstract     = {<p>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.</p>},
  author       = {Niska-Blakie, Joanna and Gopinathan, Lakshmi and Low, Kia Ngee and Kien, Yang Lay and Goh, Christine M.F. and Caldez, Matias J. and Pfeiffenberger, Elisabeth and Jones, Oliver S. and Ong, Chee Bing and Kurochkin, Igor V. and Coppola, Vincenzo and Tessarollo, Lino and Choi, Hyungwon and Kanagasundaram, Yoganathan and Eisenhaber, Frank and Maurer-Stroh, Sebastian and Kaldis, Philipp},
  issn         = {1420-682X},
  language     = {eng},
  publisher    = {Birkhäuser Verlag},
  series       = {Cellular and Molecular Life Sciences},
  title        = {Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype},
  url          = {http://dx.doi.org/10.1007/s00018-019-03359-z},
  doi          = {10.1007/s00018-019-03359-z},
  year         = {2019},
}