title: Metabolite profiles reveal energy failure and impaired beta-oxidation in liver of mice with complex III deficiency due to a BCS1L mutation.
abstract: OBJECTIVE
  Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics.
  
  
  METHODS
  With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants.
  
  
  RESULTS
  Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease.
  
  
  CONCLUSIONS
  The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions.
authors: Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
authors: Heike
authors: H
authors: Kotarsky
authors: Matthias
authors: M
authors: Keller
authors: Mina
authors: M
authors: Davoudi
authors: Per
authors: P
authors: Levéen
authors: Riitta
authors: R
authors: Karikoski
authors: David P
authors: DP
authors: Enot
authors: Vineta
authors: V
authors: Fellman
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics; D005650:Fumarates / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D000975:Antioxidants; C518901:BCS1L protein, mouse; D005650:Fumarates; D018832:Molecular Chaperones; D000249:Adenosine Monophosphate; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D000074183:ATPases Associated with Diverse Cellular Activities; D014450:Electron Transport Complex III