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 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.
Highlights
Mitochondrial disorders are caused by mutations or deletions in mitochondrial or nuclear DNA affecting the respiratory chain or other mitochondrial functions
Entire litters were randomized to receive either high carbohydrate diet (HCD) or standard diet (SD), and for each homozygous (Bcs1lG/G) mouse a littermate gender-matched wild-type (WT) or heterozygous (Bcs1lA/G) mouse was chosen as a control animal (n = 51, of which 26 males)
The homozygous mice had low blood glucose and high lactate-to-glucose ratio, which was unchanged by the increased dietary dextrose (Table 1)
Summary
Mitochondrial disorders are caused by mutations or deletions in mitochondrial (mtDNA) or nuclear (nDNA) DNA affecting the respiratory chain or other mitochondrial functions. Several neonatal mitochondrial disorders present with fetal growth restriction associated with hepatopathy and energy failure, and recently many causative mutations have been identified in specific genes such as BCS1L, DGUOK, MPV17, POLG, SCO1, and TFAM [1,2,3]. BCS1L mutations are the most common cause for CIII dysfunction [4]. The most severe BCS1L-related disorder is GRACILE syndrome that manifests as fetal onset growth restriction, aminoaciduria due to proximal tubulopathy, hepatopathy with cholestasis and iron overload, lactic acidosis, and early death [5,6,7]. BCS1L is an assembly factor for respiratory chain (RC) complex III (CIII), needed for the incorporation of the electron-transferring subunit Rieske iron-sulfur protein (RISP) into the complex
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