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

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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; Kurochkin, Igor V.; Coppola, Vincenzo; Tessarollo, Lino; Choi, Hyungwon; Kanagasundaram, Yoganathan; Eisenhaber, Frank; Maurer-Stroh, Sebastian; Kaldis, Philipp.

I: Cellular and Molecular Life Sciences, 11.2019.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Niska-Blakie, J, Gopinathan, L, Low, KN, Kien, YL, Goh, CMF, Caldez, MJ, Pfeiffenberger, E, Jones, OS, Ong, CB, Kurochkin, IV, Coppola, V, Tessarollo, L, Choi, H, Kanagasundaram, Y, Eisenhaber, F, Maurer-Stroh, S & Kaldis, P 2019, 'Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype', Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-019-03359-z

APA

CBE

Niska-Blakie J, Gopinathan L, Low KN, Kien YL, Goh CMF, Caldez MJ, Pfeiffenberger E, Jones OS, Ong CB, Kurochkin IV, Coppola V, Tessarollo L, Choi H, Kanagasundaram Y, Eisenhaber F, Maurer-Stroh S, Kaldis P. 2019. Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-019-03359-z

MLA

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Author

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 ; Kurochkin, Igor V. ; Coppola, Vincenzo ; Tessarollo, Lino ; Choi, Hyungwon ; Kanagasundaram, Yoganathan ; Eisenhaber, Frank ; Maurer-Stroh, Sebastian ; Kaldis, Philipp. / Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype. I: Cellular and Molecular Life Sciences. 2019.

RIS

TY - JOUR

T1 - Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype

AU - Niska-Blakie, Joanna

AU - Gopinathan, Lakshmi

AU - Low, Kia Ngee

AU - Kien, Yang Lay

AU - Goh, Christine M.F.

AU - Caldez, Matias J.

AU - Pfeiffenberger, Elisabeth

AU - Jones, Oliver S.

AU - Ong, Chee Bing

AU - Kurochkin, Igor V.

AU - Coppola, Vincenzo

AU - Tessarollo, Lino

AU - Choi, Hyungwon

AU - Kanagasundaram, Yoganathan

AU - Eisenhaber, Frank

AU - Maurer-Stroh, Sebastian

AU - Kaldis, Philipp

PY - 2019/11

Y1 - 2019/11

N2 - 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.

AB - 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.

KW - C7orf10

KW - Glutaric aciduria type 3 (GA3)

KW - Gut microflora

KW - Lipids

KW - Metabolomics

KW - Obesity

KW - Sugct

UR - http://www.scopus.com/inward/record.url?scp=85074986360&partnerID=8YFLogxK

U2 - 10.1007/s00018-019-03359-z

DO - 10.1007/s00018-019-03359-z

M3 - Article

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

SN - 1420-9071

ER -