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. Previous studies have shown that the transfection of the VHL gene in VHL-deficient cells originating from CCRCs could suppress their ability to form tumors when they were injected into nude mice. However, various additional genetic alterations are observed in such cancer cells. In order to investigate whether VHL invalidation was related to the mitochondrial impairment, we have studied the effects of wild-type VHL transfection into VHL-deficient 786-0 or RCC10 cells on their oxidative phosphorylation (OXPHOS) subunit contents and functions. We show that the presence of wild-type VHL protein (pVHL) increased mitochondrial DNA and respiratory chain protein contents and permitted the cells to rely on their mitochondrial ATP production to grow in the absence of glucose. In parallel to mtDNA increase, the presence of pVHL up regulated the mitochondrial transcription factor A, as shown by western blot analysis. In conclusion, in CCRCs, pVHL deficiency is one of the factors responsible for down-regulation of the biogenesis of OXPHOS complexes.
Hervouet
Eric
E
Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Centre National de la Recherche Scientifique-Université Claude Bernard de Lyon 1, F-69622 Villeurbanne, France.
Demont
Jocelyne
J
Pecina
Petr
P
Vojtísková
Alena
A
Houstek
Josef
J
Simonnet
Hélène
H
Godinot
Catherine
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D017931:DNA Primers; D004272:DNA, Mitochondrial; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human