Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency.
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.
Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland. jayasimman.rajendran@helsinki.fi.|Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland. jayasimman.rajendran@helsinki.fi.
Jayasimman
J
Rajendran
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. nikica.tomasic@med.lu.se.|Department of Neonatology, Karolinska University Hospital, 17176 Solna, Sweden. nikica.tomasic@med.lu.se.
Nikica
N
Tomašić
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. heike.kotarsky@gmail.com.
Heike
H
Kotarsky
Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. eva.hansson@med.lu.se.
Eva
E
Hansson
Finnish Institute of Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland. vidya.velagapudi@helsinki.fi.
Vidya
V
Velagapudi
Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland. jukka.kallijarvi@helsinki.fi.
Jukka
J
Kallijärvi
Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00014 Helsinki, Finland. vineta.fellman@med.lu.se.|Department of Clinical Sciences, Lund, Pediatrics, Lund University, 22185 Lund, Sweden. vineta.fellman@med.lu.se.|Institute of Clinical medicine, Children's Hospital, Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland. vineta.fellman@med.lu.se.
Vineta
V
Fellman
D000074183:ATPases Associated with Diverse Cellular Activities; D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D000818:Animals; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000494:pharmacology*; D014450:Electron Transport Complex III / Q000172:deficiency / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods*; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000097:blood / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D025341:Principal Component Analysis; D014508:Urea / Q000378:metabolism
D000596:Amino Acids; C518901:BCS1L protein, mouse; D004040:Dietary Carbohydrates; D008112:Liver Glycogen; D018832:Molecular Chaperones; D014508:Urea; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III
BCS1L; GRACILE syndrome; dextrose diet; metabolite; mitochondrial disorder; mouse model; nutrition