title: Genome instability in Maple Syrup Urine Disease correlates with impaired mitochondrial biogenesis.
abstract: OBJECTIVE
  The mitochondrial branched-chain ketoacid dehydrogenase (BCKD) catalyzes the degradation of branched-chain amino acids (BCAA), which have been shown to induce oxidative stress. Maple Syrup Urine Disease (MSUD) is caused by impaired activity of BCKD, suggesting that oxidative stress and resulting DNA damage could contribute to pathology. We evaluated the potential effect of BCKD deficiency on genome integrity and mitochondrial function as a downstream target.
  
  
  METHODS
  Primary fibroblasts from MSUD patients and controls were either cultivated under normal conditions or exposed to metabolic or oxidative stress. DNA was analyzed for damage and mitochondrial function was evaluated by gene expression analyses, functional assays and immunofluorescent methods.
  
  
  RESULTS
  Patient fibroblasts accumulated damage in mitochondrial DNA (mtDNA) and nuclear DNA, with a corresponding reduction in mitochondrial transcription, mtDNA copy number and pyruvate dehydrogenase. We found no evidence of increased level of reactive oxygen species (ROS) in patient fibroblasts under normal conditions, suggesting that the genotoxic effect is ascribed to accumulating metabolites.
  
  
  CONCLUSIONS
  Impaired BCKD activity as in MSUD, results in accumulation of DNA damage and corresponding mitochondrial dysfunction.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Department of Microbiology, University of Oslo, Oslo University Hospital, Oslo, Norway.
authors.forename: Janne M
authors.initials: JM
authors.lastname: Strand
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
authors.forename: Ragnhild
authors.initials: R
authors.lastname: Skinnes
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Department of Microbiology, University of Oslo, Oslo University Hospital, Oslo, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Women and Children's Division, Oslo University Hospital, Oslo, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Rootvelt
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
authors.forename: Berit
authors.initials: B
authors.lastname: Woldseth
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Department of Microbiology, University of Oslo, Oslo University Hospital, Oslo, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. Electronic address: lars.eide@medisin.uio.no.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D004249:DNA Damage; D017931:DNA Primers; D042822:Genomic Instability; D006801:Humans; D008375:Maple Syrup Urine Disease / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D000597:Amino Acids, Branched-Chain; D017931:DNA Primers
keywords: BCKA; DNA damage; MSUD; PDH; mitochondrial biogenesis