Pathologies liées aux déficits du cycle de Krebs

Abstract

In humans, dysfunctions of Krebs cycle enzymes caused by genetic mutations result either in severe encephalopathies of the young child, or in the appearance of different types of tumors and cancers affecting diverse organs. Thus mutations of the succinate dehydrogenase genes have been identified in familial forms of pheochromocytomas and paragangliomas. Most of the mutations in the fumarase gene are found in uterine leiomyomas in association with renal cancers, but cases of childhood encephalopathies have also been observed resulting from mutations affecting the same gene. Isocitrate dehydrogenase gene mutations account for up to 20% of acute myeloid leukemias, and up to 80% in some gliomas. So far we cannot explain the diversity of the possible consequences of these mutations : encephalopathies versus cancers, the different tissues that are affected and the variable kinetics of appearance of symptoms. On the other hand, it seems now established that the abnormalities in the metabolic equilibria that result from these mutations are at the basis of the tumor processes by modulating the activity of a number of hydroxylases that may affect the fate of certain transcription factors, but also the DNA and histone methylation. In this context, it seems surprising that some fungicides that are now widely used, block a central stage of the Krebs cycle, namely the succinate dehydrogenase. The principle of precaution would impose to urgently re-evaluate the need for the use of these substances in consideration of human health and the environment.