Unsuspected task for an old team: succinate, fumarate and other Krebs cycle acids in metabolic remodeling.
Seventy years from the formalization of the Krebs cycle as the central metabolic turntable sustaining the cell respiratory process, key functions of several of its intermediates, especially succinate and fumarate, have been recently uncovered. The presumably immutable organization of the cycle has been challenged by a number of observations, and the variable subcellular location of a number of its constitutive protein components is now well recognized, although yet unexplained. Nonetheless, the most striking observations have been made in the recent period while investigating human diseases, especially a set of specific cancers, revealing the crucial role of Krebs cycle intermediates as factors affecting genes methylation and thus cell remodeling. We review here the recent advances and persisting incognita about the role of Krebs cycle acids in diverse aspects of cellular life and human pathology.
Hôpital Robert Debré, INSERM, UMR1141, Paris 75019, France; U.F.R. de Médecine Université Paris Diderot, Paris 75019, France.
Paule
P
Bénit
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France.
Eric
E
Letouzé
Hôpital Robert Debré, INSERM, UMR1141, Paris 75019, France; U.F.R. de Médecine Université Paris Diderot, Paris 75019, France.
Malgorzata
M
Rak
UEVE UMR 861, I-Stem, AFM, Evry, France.
Laetitia
L
Aubry
Paris-Cardiovascular Research Center (PARCC), INSERM, UMR970, Paris 75015, France; Faculté de Médecine, Université Paris Descartes, Paris 75006, France.
Nelly
N
Burnichon
Paris-Cardiovascular Research Center (PARCC), INSERM, UMR970, Paris 75015, France; Faculté de Médecine, Université Paris Descartes, Paris 75006, France.
Judith
J
Favier
Paris-Cardiovascular Research Center (PARCC), INSERM, UMR970, Paris 75015, France; Faculté de Médecine, Université Paris Descartes, Paris 75006, France.
Anne-Paule
AP
Gimenez-Roqueplo
Hôpital Robert Debré, INSERM, UMR1141, Paris 75019, France; U.F.R. de Médecine Université Paris Diderot, Paris 75019, France. Electronic address: pierre.rustin@inserm.fr.
Pierre
P
Rustin
D002952:Citric Acid Cycle; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism; D005650:Fumarates / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D060847:Metabolic Engineering; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D019802:Succinic Acid / Q000737:chemistry / Q000378:metabolism*
D005650:Fumarates; C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019802:Succinic Acid; D049308:Dioxygenases; D013385:Succinate Dehydrogenase
Dioxygenase; HIF1α; Histone; Mitochondria; Tricarboxylic acid cycle