HIF and reactive oxygen species regulate oxidative phosphorylation in cancer.

A decrease in oxidative phosphorylation (OXPHOS) is characteristic of many cancer types and, in particular, of clear cell renal carcinoma (CCRC) deficient in von Hippel-Lindau (vhl) gene. In the absence of functional pVHL, hypoxia-inducible factor (HIF) 1-alpha and HIF2-alpha subunits are stabilized, which induces the transcription of many genes including those involved in glycolysis and reactive oxygen species (ROS) metabolism. Transfection of these cells with vhl is known to restore HIF-alpha subunit degradation and to reduce glycolytic genes transcription.

Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma.

Mutations in mitochondrial DNA (mtDNA) are frequent in cancers but it is not yet clearly established whether they are modifier events involved in cancer progression or whether they are a consequence of tumorigenesis. Here we show a benign tumor type in which mtDNA mutations that lead to complex I (CI) enzyme deficiency are found in all tumors and are the only genetic alteration detected. Actually renal oncocytomas are homogeneous tumors characterized by dense accumulation of mitochondria and we had found that they are deficient in electron transport chain complex I (CI, NADH-ubiquinone oxidoreductase).

Inhibition of cytochrome c oxidase subunit 4 precursor processing by the hypoxia mimic cobalt chloride.

Cobalt is often used as a hypoxia mimic in cell culture, because it stabilizes the alpha subunits of the transcription factor, HIF (hypoxia-inducible factor). We have previously shown that HIF stabilization due to a deficiency of the von Hippel Lindau protein (pVHL) in clear cell renal carcinoma (CRCC) was correlated to a down-regulation of oxidative phosphorylation. To better understand this mechanism, we have used CoCl2 in CRCC expressing stably transfected vhl.

Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules.

Hypoxia has been suspected to trigger transdifferentiation of renal tubular cells into myofibroblasts in an epithelial-to-mesenchymal transition (EMT) process. To determine the functional networks potentially altered by hypoxia, rat renal tubule suspensions were incubated under three conditions of oxygenation ranging from normoxia (lactate uptake) to severe hypoxia (lactate production). Transcriptome changes after 4 h were analyzed on a high scale by restriction fragment differential display.

A new role for the von Hippel-Lindau tumor suppressor protein: stimulation of mitochondrial oxidative phosphorylation complex biogenesis.

Although mitochondrial deficiency in cancer has been described by Warburg, many years ago, the mechanisms underlying this impairment remain essentially unknown. Many types of cancer cells are concerned and, in particular, clear cell renal carcinoma (CCRC). In this cancer, the tumor suppressor gene, VHL (von Hippel-Lindau factor) is invalidated.

Mitochondrial complex I is deficient in renal oncocytomas.

Renal oncocytomas are benign tumors characterized by dense accumulation of mitochondria the cause of which remains unknown so far. Consistently, mitochondrial DNA content and the amounts and catalytic activities of several oxidative phosphorylation (OXPHOS) complexes were known to be increased in these tumors, but it was not ascertained that the OXPHOS system was functional. Here we investigated mitochondrial complex I and found that its NADH dehydrogenase activity and protein content were specifically decreased in oncocytomas, in stark contrast with the parallel decrease of all respiratory chain complexes in other, malignant, renal tumors.

Origin and history of the IVS-I-110 and codon 39 beta-thalassemia mutations in the Lebanese population.

Using restriction fragment length polymorphisms (RFLPs) and sequence haplotype analysis, we studied the chromosomal background of the beta-globin gene in 31 unrelated Lebanese IVS-I-110 or codon 39 (Cd39) subjects, and five normal betaAbeta/A individuals. Our results are compared with those from similar studies in other parts of the Mediterranean in an attempt to provide insights into historical patterns of selection and disease. The great majority of the Lebanese chromosomes with the IVS-I-110 mutation are associated with the RFLP haplotype I and sequence haplotype HT1, which is probably the ancestral structure on which the mutation first emerged.

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

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.

Isolation and characterization of Urbain, a 20-hydroxyecdysone-inducible gene expressed during morphogenesis of Bombyx mori wing imaginal discs.

In insects, wing imaginal discs respond to the steroid hormone 20-hydroxyecdysone by initiating morphogenesis leading to the formation of the adult flight appendages. In this work we analyse the expression of a Bombyx gene, referred to as Urbain, whose cDNA had been previously isolated from wing discs (Chareyre et al. 1993).