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Human Molecular Genetics Advance Access published online on September 29, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi359
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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received July 12, 2005
Revised September 7, 2005
Accepted September 21, 2005

Article

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

Jean-Jacques Brière 1, Judith Favier 2, Paule Bénit 1, Vincent El Ghouzzi 1, Annalisa Lorenzato 3, Daniel Rabier 4, Maria Flavia Di Renzo 3, Anne-Paule Gimenez-Roqueplo 5, and Pierre Rustin 6*

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

* To whom correspondence should be addressed.
Pierre Rustin, E-mail: rustin{at}rdebre.inserm.fr


  Abstract

The genes encoding succinate dehydrogenase (SDH) subunits B, C, and D, act as tumour suppressors in neuroendocrine 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 inhibits this nuclear translocation. Therefore, the pseudo-hypoxia pathway in SDH-deficient cells depends on the HIF1{alpha} prolyl hydroxylase product/substrate (succinate/{alpha}-ketoglutarate) equilibrium. In SDH deficiency, organic acids thus appear instrumental in the HIF1{alpha}-dependent cascade suggesting a direct link between SDH and tumorigenesis.


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