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. We show that, in addition to its effect on HIF-alpha subunits, CoCl2 prevented the normal processing of the precursor of cytochrome c oxidase (COX) subunit 4 and induced COX degradation very likely by inhibiting the mitochondrial intermediate peptidase (MIP) that cleaves the COX4 precursor protein. This cobalt-induced MIP inhibition was however not observed in other human mitochondrial precursor sequences as previously predicted from comparison between human and yeast mitochondrial precursor sequences.
Hervouet
Eric
E
Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Centre National de la Recherche Scientifique-Université Claude Bernard de Lyon 1-69622 Villeurbanne, France.
Pecina
Petr
P
Demont
Jocelyne
J
Vojtísková
Alena
A
Simonnet
Hélène
H
Houstek
Josef
J
Godinot
Catherine
C
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D003035:Cobalt / Q000633:toxicity*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced* / Q000201:enzymology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010085:Oxidative Phosphorylation / Q000187:drug effects; D021122:Protein Subunits; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D021122:Protein Subunits; D003035:Cobalt; D003576:Electron Transport Complex IV; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008666:Metalloendopeptidases; C068038:mitochondrial intermediate peptidase; C497446:VHL protein, human; C018021:cobaltous chloride