Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency

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Rajendran , J , Tomasic , N , Kotarsky , H , Hansson , E , Velagapudi , V , Kallijarvi , J & Fellman , V 2016 , ' Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency ' International Journal of Molecular Sciences , vol. 17 , no. 11 , 1824 . DOI: 10.3390/ijms17111824

Title: Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency
Author: Rajendran, Jayasimman; Tomasic, Nikica; Kotarsky, Heike; Hansson, Eva; Velagapudi, Vidya; Kallijarvi, Jukka; Fellman, Vineta
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Children's Hospital
Date: 2016-11
Language: eng
Number of pages: 13
Belongs to series: International Journal of Molecular Sciences
ISSN: 1422-0067
URI: http://hdl.handle.net/10138/172711
Abstract: Mitochondrial disorders cause energy failure and metabolic derangements. Metabolome profiling in patients and animal models may identify affected metabolic pathways and reveal new biomarkers of disease progression. Using liver metabolomics we have shown a starvation-like condition in a knock-in (Bcs1l(c.232A>G)) mouse model of GRACILE syndrome, a neonatal lethal respiratory chain complex III dysfunction with hepatopathy. Here, we hypothesized that a high-carbohydrate diet (HCD, 60% dextrose) will alleviate the hypoglycemia and promote survival of the sick mice. However, when fed HCD the homozygotes had shorter survival (mean +/- SD, 29 +/- 2.5 days, n = 21) than those on standard diet (33 +/- 3.8 days, n = 30), and no improvement in hypoglycemia or liver glycogen depletion. We investigated the plasma metabolome of the HCD- and control diet-fed mice and found that several amino acids and urea cycle intermediates were increased, and arginine, carnitines, succinate, and purine catabolites decreased in the homozygotes. Despite reduced survival the increase in aromatic amino acids, an indicator of liver mitochondrial dysfunction, was normalized on HCD. Quantitative enrichment analysis revealed that glycine, serine and threonine metabolism, phenylalanine and tyrosine metabolism, and urea cycle were also partly normalized on HCD. This dietary intervention revealed an unexpected adverse effect of high-glucose diet in complex III deficiency, and suggests that plasma metabolomics is a valuable tool in evaluation of therapies in mitochondrial disorders.
Subject: mitochondrial disorder
BCS1L
mouse model
metabolite
dextrose diet
nutrition
GRACILE syndrome
CHRONIC KIDNEY-DISEASE
TRYPTOPHAN-KYNURENINE
OXIDATIVE STRESS
IRON-OVERLOAD
BCS1L GENE
HIGH-FAT
INFLAMMATION
HEART
DISORDERS
MUTATION
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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