Abstract
Tet3 is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How αKG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an unresolved question in the connection between metabolism and epigenetics. We show that in neurons the mitochondrial enzyme glutamate dehydrogenase, which converts glutamate into αKG in an NAD+-dependent manner, is redirected to the nucleus by the αKG-consumer protein Tet3, suggesting on-site production of αKG. Further, glutamate dehydrogenase has a stimulatory effect on Tet3 demethylation activity in neurons, and neuronal activation increases the levels of αKG. Overall, the glutamate dehydrogenase-Tet3 interaction might have a role in epigenetic changes during neural plasticity.
Highlights
Tet[3] is the main α-ketoglutarate-dependent dioxygenase in neurons that converts 5methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC
Our data confirm that neuronal glutamate dehydrogenase (Gdh) has a split spatial distribution with a substantial fraction of the protein being redirected to the nucleus, probably before entering the mitochondria
This puts Gdh in line with other mitochondrial proteins, such as the pyruvate dehydrogenase complex (PDC) or enzymes of the tricarboxylic acid (TCA) cycle that can be translocated to the nucleus for controlled intranuclear metabolite biosynthesis and metabolic regulation of gene expression by changing histone modifications[21,56]
Summary
Tet[3] is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. The mdC-oxidation products hmdC, fdC, and cadC are generated by ten eleven translocation enzymes (Tet1-3), which are themselves α-ketoglutarate (αKG)- and oxygen-dependent dioxygenases (Fig. 1a). HmdC levels are by far the highest in brain[9,10], and in particular found in synapse-related genes of neurons[11] This correlates with high Tet expression levels in neurons[12], further suggesting that dynamic oxidation-dependent active DNA demethylation is an essential prerequisite for neuronal plasticity[13,14]. Acetyl-CoA is produced by the pyruvate dehydrogenase complex (PDC), which is shuttled from mitochondria into the nucleus[21] This moonlighting of mitochondrial and cytosolic protein echoforms into the nucleus is a new principle that establishes the nucleus as a biosynthetically active entity[22] controlled by metabolic fluctuations that can differ substantially within the cell[23]. We show that neuronal Tet[3] redirects the mitochondrial enzyme Gdh into the nucleus to establish an intranuclear production of αKG from NAD+ and glutamate
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