Chromosome conformation capture of transcriptional interactions between cytochrome c oxidase genes and genes of glutamatergic synaptic transmission in neurons.

Neuronal activity and energy metabolism are tightly coupled processes. Recently, we found that nuclear respiratory factor 1 co-regulates all subunits of cytochrome c oxidase (COX, representing oxidative energy metabolism) and glutamatergic neurochemicals, including NR1 (Grin1) and NR2B (Grin2b) of NMDA receptors, GluR2 (Gria2) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and neuronal nitric oxide synthase (Nos1). Moreover, all 10 nuclear-encoded COX subunit genes and three transcription factor genes for the three mitochondrial-encoded COX subunits are transcribed in the same transcription factory. The goal of the present study was to test our hypothesis that genomic loci for Grin1, Grin2b, Gria2, and Nos1 interact with those for COX at the transcriptional level. By means of chromosome conformation capture, interactions were found among all of these genes in neurons, but not in C2C12 muscle cells. COX subunit genes also did not interact with neurochemical genes not regulated by nuclear respiratory factor 1, nor with genes for calreticulin, a non-mitochondrial protein. Depolarizing stimulation up-regulated interaction frequencies between COX and neurochemical genes, whereas impulse blockade with tetrodotoxin or inhibition of COX with KCN down-regulated them in neurons. Thus, an efficient mechanism is in place for coordinating the transcriptional coupling of energy metabolism and glutamatergic neurotransmission at the molecular level in neurons.