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Int. J. Mol. Sci. 2016, 17(11), 1824;

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

Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland
Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden
Department of Neonatology, Karolinska University Hospital, 17176 Solna, Sweden
Finnish Institute of Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland
Institute of Clinical medicine, Children’s Hospital, Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland
Author to whom correspondence should be addressed.
Academic Editor: Anthony Lemarié
Received: 12 August 2016 / Revised: 24 September 2016 / Accepted: 24 October 2016 / Published: 1 November 2016
(This article belongs to the Special Issue Metabolomic Technologies in Medicine)
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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 (Bcs1lc.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. View Full-Text
Keywords: mitochondrial disorder; BCS1L; mouse model; metabolite; dextrose diet; nutrition; GRACILE syndrome mitochondrial disorder; BCS1L; mouse model; metabolite; dextrose diet; nutrition; GRACILE syndrome

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Rajendran, J.; Tomašić, N.; Kotarsky, H.; Hansson, E.; Velagapudi, V.; Kallijärvi, J.; Fellman, V. Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency. Int. J. Mol. Sci. 2016, 17, 1824.

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