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Effect of high-carbohydrate diet on plasma metabolome in mice with mitochondrial respiratory chain complex III deficiency

Rajendran, Jayasimman; Tomasic, Nikica LU ; Kotarsky, Heike LU ; Hansson, Eva LU ; Velagapudi, Vidya; Kallijärvi, Jukka LU and Fellman, Vineta LU (2016) In International Journal of Molecular Sciences 17(11).
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 (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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BCS1L, Dextrose diet, GRACILE syndrome, Metabolite, Mitochondrial disorder, Mouse model, Nutrition
in
International Journal of Molecular Sciences
volume
17
issue
11
publisher
MOLECULAR DIVERSITY PRESERVATION INT
external identifiers
  • scopus:84994494535
  • wos:000388809600058
ISSN
1661-6596
DOI
10.3390/ijms17111824
language
English
LU publication?
yes
id
41264cbf-f19a-4fd6-83fc-e728e0292459
date added to LUP
2016-12-05 14:05:02
date last changed
2017-09-18 11:30:15
@article{41264cbf-f19a-4fd6-83fc-e728e0292459,
  abstract     = {<p>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<sup>c.232A&gt;G</sup>) 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.</p>},
  articleno    = {1824},
  author       = {Rajendran, Jayasimman and Tomasic, Nikica and Kotarsky, Heike and Hansson, Eva and Velagapudi, Vidya and Kallijärvi, Jukka and Fellman, Vineta},
  issn         = {1661-6596},
  keyword      = {BCS1L,Dextrose diet,GRACILE syndrome,Metabolite,Mitochondrial disorder,Mouse model,Nutrition},
  language     = {eng},
  month        = {11},
  number       = {11},
  publisher    = {MOLECULAR DIVERSITY PRESERVATION INT},
  series       = {International Journal of Molecular Sciences},
  title        = {Effect of high-carbohydrate diet on plasma metabolome in mice with mitochondrial respiratory chain complex III deficiency},
  url          = {http://dx.doi.org/10.3390/ijms17111824},
  volume       = {17},
  year         = {2016},
}