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

Abstract

A mechanism decreasing oxidative metabolism during normal cell division and growth is expected to direct substrates toward biosyntheses rather than toward complete oxidation to CO(2). 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 F(1)-ATPase activity was not consistently decreased and its impairment was associated with increased aggressiveness in CCRCCs. Immunodetection of free F(1)-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.

Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors

“…All of the disruptive mutations were concentrated in complex I subunits, whereas analysis of the corresponding samples from the normal adjacent tissue showed the somatic origin of the mutations in all cases. This finding further supports the hypothesis that dysfunction of complex I may play a role in tumor development, as previously proposed for thyroid (10) and renal oncocytoma (15,16).…”

“…Several authors have performed gene expression and biochemical studies to investigate molecular aspects of this specific histological phenotype (13,14). In particular, deficient complex I activity has been described in renal oncocytoma (15,16), and a correlation between mitochondrial hyperplasia and tumorigenesis has been suggested (17). Most mtDNA changes reported in thyroid oncocytic tumors have been identified after partial sequencing of the mitochondrial genome, again without proven pathogenicity (18,19).…”

Mitochondrial DNA content in paired normal and cancerous breast tissue samples from patients with breast cancer

“…It was hypothesised that mitochondrial respiratory dysfunction and damage of mtDNA, such as mutation, deletion or depletion, in carcinogenesis may course the quantitative alterations (Ye et al 2008). Those alterations of mtDNA could correlate with increased risk (Mosquera-Miguel et al 2008;Bai et al 2007) and increased invasiveness of cancer (Simonnet et al 2002). Decreased mtDNA content can cause decreased oxidative phosphorylation capacity that could increase cancer cell growth under hypoxic conditions during cancer development and cancer progression (Rossignol et al 2004).…”

Cancer as a Metabolic Disease

“…Their results showed a drop in the β-F1-ATPase/Hsp60 ratio concurrent with an upregulation of the glyceraldehyde-3-phosphate dehydrogenase potential in most common human tumors [72]. These and other observations indicate that the bioenergetic capacity of tumor cells is largely defective [87][88][89]. Viewed collectively, the bulk of the experimental evidence indicates that mitochondria structure and function is abnormal in cancer cells.…”