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Human Molecular Genetics Advance Access originally published online on September 29, 2005
Human Molecular Genetics 2005 14(21):3263-3269; doi:10.1093/hmg/ddi359
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mitochondrial succinate is instrumental for HIF1{alpha} nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions

Jean-Jacques Brière1, Judith Favier2, Paule Bénit1, Vincent El Ghouzzi1, Annalisa Lorenzato3, Daniel Rabier4, Maria Flavia Di Renzo3, Anne-Paule Gimenez-Roqueplo2,5 and Pierre Rustin1,*

1INSERM U676, Hôpital Robert Debré, 48 boulevard Serurier, 75019 Paris, France, 2INSERM U36, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France, 3Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, Str Provinciale 142, Km 3.95, 10060 Candiolo, Turin, Italy, 4Laboratoire de Biochimie A, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France and 5Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, Assistance Publique/Hôpitaux de Paris, 75015 Paris, France

* To whom correspondence should be addressed at: INSERM U676, Bâtiment Ecran, Hôpital Robert Debré, 48 boulevard Serurier, 75019 Paris, France. Tel: +33 140031989; Fax: +33 140031978; Email: rustin{at}rdebre.inserm.fr

Received July 12, 2005; Revised September 7, 2005; Accepted September 21, 2005

The genes encoding succinate dehydrogenase (SDH) subunits B, C and D, act as tumour suppressors in neuro-endocrine tissues. Tumour formation has been associated with succinate accumulation. In paraganglioma cells, two forms of SDHA (type I, II) were found which might preclude significant succinate accumulation in the case of a mutation in either form. In fibroblasts only SDHA type I is found. In these cells, SDHA type I mutation leads to SDH deficiency, succinate accumulation and hypoxia-inducible factor 1{alpha}(HIF1{alpha}) nuclear translocation. HIF1{alpha} nuclear translocation was not observed in ATPase-deficient fibroblasts with increased superoxide production and was found to be independent of cellular iron availability in SDHA-mutant cells. This suggests that neither superoxides nor iron were causative of HIF1{alpha} nuclear translocation. Conversely, {alpha}-ketoglutarate ({alpha}-KG) inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1{alpha}prolyl hydroxylase product/substrate (succinate/{alpha}-KG) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1{alpha}-dependent cascade suggesting a direct link between SDH and tumourigenesis.


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