Krebs cycle dysfunction shapes epigenetic landscape of chromatin: novel insights into mitochondrial regulation of aging process.
Although there is a substantial literature that mitochondria have a crucial role in the aging process, the mechanism has remained elusive. The role of reactive oxygen species, mitochondrial DNA injuries, and a decline in mitochondrial quality control has been proposed. Emerging studies have demonstrated that Krebs cycle intermediates, 2-oxoglutarate (also known as α-ketoglutarate), succinate and fumarate, can regulate the level of DNA and histone methylation. Moreover, citrate, also a Krebs cycle metabolite, can enhance histone acetylation. Genome-wide screening studies have revealed that the aging process is linked to significant epigenetic changes in the chromatin landscape, e.g. global demethylation of DNA and histones and increase in histone acetylation. Interestingly, recent studies have revealed that the demethylases of DNA (TET1-3) and histone lysines (KDM2-7) are members of 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzymes are activated by oxygen, iron and the major Krebs cycle intermediate, 2-oxoglutarate, whereas they are inhibited by succinate and fumarate. Considering the endosymbiont origin of mitochondria, it is not surprising that Krebs cycle metabolites can control the gene expression of host cell by modifying the epigenetic landscape of chromatin. It seems that age-related disturbances in mitochondrial metabolism can induce epigenetic reprogramming, which promotes the appearance of senescent phenotype and degenerative diseases.
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. Electronic address: antero.salminen@uef.fi.
Antero
A
Salminen
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box, FIN-70211 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
Kai
K
Kaarniranta
Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
Mikko
M
Hiltunen
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box, FIN-70211 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
Anu
A
Kauppinen
D000375:Aging / Q000235:genetics* / Q000502:physiology; D002843:Chromatin / Q000235:genetics*; D002952:Citric Acid Cycle / Q000235:genetics*; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases / Q000378:metabolism; D044127:Epigenesis, Genetic; D005650:Fumarates / Q000378:metabolism; D006657:Histones / Q000235:genetics; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000502:physiology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; D005650:Fumarates; D006657:Histones; D007656:Ketoglutaric Acids; D011518:Proto-Oncogene Proteins; D004247:DNA; D019802:Succinic Acid; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases
2-Oxoglutarate; Aging; Energy metabolism; Epigenetics; Jumonji; Methylation