ReviewKrebs cycle intermediates regulate DNA and histone methylation: Epigenetic impact on the aging process
Introduction
Mitochondria are major powerhouses in cellular energy production although they have several other regulatory functions which are linked to the control of energy metabolism (McBride et al., 2006, Detmer and Chan, 2007). It was recognized over a century ago that there is an inverse correlation between the metabolic rate and the lifespan of animals (see Hulbert et al., 2007). The rate-of-living-theory of aging emphasizes the fundamental role of energy metabolism in the aging process. Subsequently, a plethora of theories have been proposed to try to explain this phenomenon, such as free radical theory of aging (Harman, 1956) and mitochondrial DNA mutation theory (Fleming et al., 1982). However, it seems that these theories are not sufficient to elucidate the close connection of the energy metabolism to the healthspan and lifespan of mammals. More recent studies have indicated that Sirtuins, class III protein deacetylases, could be the key enzymes since their activity is dependent on NAD+ and acetyl-CoA, linked to the level of energy metabolism, and moreover, SIRT3, SIRT4 and SIRT5 are located in mitochondria (Guarente, 2008, Houtkooper et al., 2012, Sack and Finkel, 2012). Sirtuins have a crucial role in the regulation of healthspan but their association to the aging process still needs to be clarified. It is also known that mitochondrial quality control declines with aging and this could provoke disturbances in the control of energy metabolism (Friguet et al., 2008). In particular, both impaired maintenance of mitochondrial proteostasis and reduced mitophagy have been hypothesized as being a source of age-related energy metabolic deficiencies (Baker et al., 2011a, Ashrafi and Schwarz, 2013).
Recent studies have indicated that mitochondrial metabolism, particularly the intermediates of Krebs cycle, can control DNA and histone methylation, which are fundamental epigenetic regulators of chromatin structure and function (Ward and Thompson, 2012, Badeaux and Shi, 2013, Kaelin and McKnight, 2013). Interestingly, both DNA and histone demethylases, removing the methyl groups from these molecules, are 2-oxoglutarate-dependent dioxygenases (2-OGDO) (McDonough et al., 2010, Loenarz and Schofield, 2011). 2-Oxoglutarate (α-ketoglutarate) is a key metabolite in the Krebs cycle (Fig. 1) but on the other hand, it is an obligatory substrate for 2-OGDO enzymes, which are critical players in conjunction with DNA and histone methyltransferases in the regulation of chromatin structure and thus in the control of gene expression. Cancer studies revealed that succinate and fumarate, also intermediates of Krebs cycle, are important inhibitors of 2-OGDO enzymes and thus their inhibitory effect potentiates DNA and histone methylation driven by DNA and histone methyltransferases (Ward and Thompson, 2012, Kaelin and McKnight, 2013). There are many indications that the aging process is regulated by epigenetic mechanisms (Han and Brunet, 2012, Huidobro et al., 2013a). As described above, it is known that changes in energy metabolism, especially those in mitochondrial metabolism, are associated with the aging process. We will first review the epigenetic mechanisms through which Krebs cycle intermediates regulate DNA and histone methylation and then evaluate their potency to control the age-related stochastic epigenetic changes which in turn promote the aging process.
Section snippets
Krebs cycle: an overview
Krebs cycle, also known as the citric acid or tricarboxylic acid cycle, is a cyclic pathway of enzymatic reactions which oxidizes the compounds derived from glucose, fatty acids and amino acids in the matrix of mitochondria (Fig. 1). The Krebs cycle involves eight steps which produce in different steps CO2 and NADH and FADH2, reduced coenzymes which transfer electrons to the respiratory chain. Subsequently, the respiratory chain generates ATP for the use in cellular processes. The chemical
2-Oxoglutarate-dependent dioxygenases control epigenetic regulation
The 2-OGDO enzymes are the largest family of nonheme oxidizing enzymes, present in animal, plants and micro-organisms (De Carolis and De Luca, 1994, Hausinger, 2004, McDonough et al., 2010). The 2-OGDO enzymes catalyze a variety of oxidation reactions, such as those involving the hydroxylation and demethylation of proteins and nucleic acids (McDonough et al., 2010, Loenarz and Schofield, 2011). These enzymes employ 2-oxoglutarate, a Krebs cycle intermediate (Fig. 1), and molecular oxygen as
Krebs cycle intermediates control 2-oxoglutarate-dependent dioxygenases
The endosymbiosis theory for the origin of eukaryotic cells proposes that there was an invasion of aerobic bacteria, e.g. α-proteobacterium, into an anaerobic archael prokaryotic host (Gray et al., 1999, Esser et al., 2004, Davidov and Jurkevitch, 2009). Later, the endosymbiont bacteria lost most of their genome to an evolving and expanding nuclear genome and it became specialized within the mitochondria, the oxidative powerhouse of the cell. Interestingly, several members of 2-OGDO family are
Epigenetic changes associated with the aging process
It has been known for 40 years that aging is linked to the changes in the methylation of DNA and histones (Vanyushin et al., 1973, Lee and Duerre, 1974). However, the role of epigenetic changes in the aging process is still a mystery, although there has been an enormous progress in research opportunities, e.g. genome-wide screening techniques, and in the understanding of the epigenetic mechanisms involved in the gene regulation (Johnson et al., 2012, D’Aquila et al., 2013, Huidobro et al., 2013a
Role of Krebs cycle metabolites in regulation of age-related epigenetic changes
The function of the Krebs cycle is dependent on several positive and negative allosteric regulators (Fig. 3A), as well as on the age-related changes at the mitochondrial morphology and dynamics (Section 2). 2-Oxoglutarate dehydrogenase is the rate-limiting enzyme and thus on the center of energy metabolic regulation. A dysfunction in the Krebs cycle flux induces an accumulation of intermediates, especially 2-oxoglutarate and succinate. These two are the Krebs cycle intermediates which can
Conclusions
Mitochondria and energy metabolism are the key elements in the regulation of life and death. It is not surprising that many aging theories propose an important role for mitochondria in the regulation of aging process. Bearing in mind the endosymbiotic origin of mitochondria, it is logical that mitochondrial factors are able to control gene expression and thus induce adaption to environmental requirements. In this respect, Krebs cycle metabolites are ideal messenger molecules in the signal
Acknowledgements
This study was financially supported by the grants from the Academy of Finland, VTR funding from Kuopio University Hospital, and strategic funding for UEFBRAIN consortium from University of Eastern Finland. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.
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