Abstract
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. To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues. 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. 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.
Highlights
Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration
To elucidate the cause of the mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and screened for Mitochondrial DNA (mtDNA) mutations in renal oncocytomas
If the samples showing residual complex I activity are compared with the activity of citrate synthase, a marker enzyme of mitochondrial energy metabolism [25], the relative enzyme activity of complex I, is
Summary
Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Otto Warburg postulated that damage of the aerobic energy metabolism is a primary and irreversible event in tumor formation [2] This hypothesis has been supported by the demonstration that mutations of single enzymes of the mitochondrial energy metabolism are associated with tumorigenesis [3, 4]. Mitochondrial DNA (mtDNA), the small genome of the mitochondrion, is essential for aerobic energy metabolism and encodes some of the subunits of respiratory chain complexes I, III, and IV, as well as the F1F0-ATP synthase. Because of its essential role in energy metabolism, the mitochondrial genome has long been suspected of contributing to metabolic alterations in tumors Such investigations date back to the 1960s, and numerous somatic mtDNA mutations have been reported in various types of human tumors (7 – 10). No other direct association of somatic mtDNA mutations with a distinct tumor type and pathophysiology has been published far [5, 13]
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