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.
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland.
Ageing Res Rev. 2014 Jul;16:45-65. doi: 10.1016/j.arr.2014.05.004. Epub 2014 Jun 5.
Many aging theories have proposed that mitochondria and energy metabolism have a major role in the aging process. There are recent studies indicating that Krebs cycle intermediates can shape the epigenetic landscape of chromatin by regulating DNA and histone methylation. A growing evidence indicates that epigenetics plays an important role in the regulation of healthspan but also is involved in the aging process. 2-Oxoglutarate (α-ketoglutarate) is a key metabolite in the Krebs cycle but it is also an obligatory substrate for 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzyme family includes the major enzymes of DNA and histone demethylation, i.e. Ten-Eleven Translocation (TETs) and Jumonji C domain containing (JmjC) demethylases. In addition, 2-OGDO members can regulate collagen synthesis and hypoxic responses in a non-epigenetical manner. Interestingly, succinate and fumarate, also Krebs cycle intermediates, are potent inhibitors of 2-OGDO enzymes, i.e. the balance of Krebs cycle reactions can affect the level of DNA and histone methylation and thus control gene expression. We will review the epigenetic mechanisms through which Krebs cycle intermediates control the DNA and histone methylation. We propose that age-related disturbances in the Krebs cycle function induce stochastic epigenetic changes in chromatin structures which in turn promote the aging process.
许多衰老理论提出，线粒体和能量代谢在衰老过程中起着重要作用。最近的研究表明，三羧酸循环中间体可以通过调节 DNA 和组蛋白甲基化来塑造染色质的表观遗传景观。越来越多的证据表明，表观遗传学在调控健康寿命方面起着重要作用，但也参与了衰老过程。2-氧戊二酸（α-酮戊二酸）是三羧酸循环中的关键代谢物，但也是 2-氧戊二酸依赖性双加氧酶（2-OGDO）的必需底物。2-OGDO 酶家族包括 DNA 和组蛋白去甲基化的主要酶，即 Ten-Eleven Translocation（TET）和 Jumonji C 结构域包含（JmjC）去甲基酶。此外，2-OGDO 成员可以以非表观遗传方式调节胶原合成和缺氧反应。有趣的是，琥珀酸和富马酸也是三羧酸循环中间体，是 2-OGDO 酶的有效抑制剂，即三羧酸循环反应的平衡可以影响 DNA 和组蛋白甲基化的水平，从而控制基因表达。我们将回顾三羧酸循环中间体通过控制 DNA 和组蛋白甲基化来控制表观遗传的机制。我们提出，与年龄相关的三羧酸循环功能障碍会导致染色质结构中的随机表观遗传变化，进而促进衰老过程。
