Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma.
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.
Mayr
Johannes A
JA
Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.
Meierhofer
David
D
Zimmermann
Franz
F
Feichtinger
Rene
R
Kögler
Christian
C
Ratschek
Manfred
M
Schmeller
Nikolaus
N
Sperl
Wolfgang
W
Kofler
Barbara
B
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
D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I