title: Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma.
abstract: OBJECTIVE
  Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking.
  
  
  METHODS
  To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues.
  
  
  RESULTS
  Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors.
  
  
  CONCLUSIONS
  Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.
authors.affiliation: Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.forename: David
authors.initials: D
authors.lastname: Meierhofer
authors.forename: Franz
authors.initials: F
authors.lastname: Zimmermann
authors.forename: Rene
authors.initials: R
authors.lastname: Feichtinger
authors.forename: Christian
authors.initials: C
authors.lastname: Kögler
authors.forename: Manfred
authors.initials: M
authors.lastname: Ratschek
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schmeller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.forename: Barbara
authors.initials: B
authors.lastname: Kofler
mesh_terms: D018249:Adenoma, Oxyphilic / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000032:analysis*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I