Journal Article

Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma

Hélène Simonnet, Nathalie Alazard, Kathy Pfeiffer, Catherine Gallou, Christophe Béroud, Jocelyne Demont, Raymonde Bouvier, Hermann Schägger and Catherine Godinot

in Carcinogenesis

Volume 23, issue 5, pages 759-768
Published in print May 2002 | ISSN: 0143-3334
Published online May 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.5.759
Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma

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A mechanism decreasing oxidative metabolism during normal cell division and growth is expected to direct substrates toward biosyntheses rather than toward complete oxidation to CO2. Hence, any event decreasing oxidative phosphorylations (OXPHOS) could provide a proliferating advantage to a transformed or tumor cell in an oxidative tissue. To test this hypothesis, we studied mitochondrial enzymes, DNA and OXPHOS protein content in three types of renal tumors from 25 patients. Renal cell carcinomas (RCCs) of clear cell type (CCRCCs) originate from the proximal tubule and are most aggressive. Chromophilic RCCs, from similar proximal origin, are less aggressive. The benign renal oncocytomas originate from collecting duct cells.

Mitochondrial enzyme and DNA contents in all tumor types or grades differed significantly from normal tissue. Mitochondrial impairment increased from the less aggressive to the most aggressive RCCs, and correlated with a considerably decreased content of OXPHOS complexes (complexes II, III, and IV of the respiratory chain, and ATPase/ATP synthase) rather than to the mitochondrial content (citrate synthase and mitochondrial (mt)DNA). In benign oncocytoma, some mitochondrial parameters (mtDNA, citrate synthase, and complex IV) were increased 4- to 7-fold, and some were slightly increased by a factor of 2 (complex V) or close to normal (complexes II and III).

A low content of complex V protein was found in all CCRCC and chromophilic tumors studied. However F1-ATPase activity was not consistently decreased and its impairment was associated with increased aggressiveness in CCRCCs. Immunodetection of free F1-sector of complex V demonstrated a disturbed assembly/stability of complex V in several CCRCC and chromophilic tumors.

All results are in agreement with the hypothesis that a decreased OXPHOS capacity favors faster growth or increased invasiveness.

Keywords: RCCs, renal cell carcinomas; CCRCCs, clear cell type renal cell carcinomas; OXPHOS, oxidative phosphorylations; VHL, von Hippel–Lindau

Journal Article.  6930 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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