Bigenomic regulation of cytochrome c oxidase in neurons and the tight coupling between neuronal activity and energy metabolism

Abstract

Cytochrome c oxidase is the terminal enzyme of the mitochondrial electron transport chain, without which oxidative metabolism cannot be carried to completion. It is one of only four unique, bigenomic proteins in mammalian cells. The holoenzyme is made up of three mitochondrial-encoded and ten nuclear-encoded subunits in a 1:1 stoichiometry. The ten nuclear subunit genes are located in nine different chromosomes. The coordinated regulation of such a multisubunit, multichromosomal, bigenomic enzyme poses a challenge. It is especially so for neurons, whose mitochondria are widely distributed in extensive dendritic and axonal processes, resulting in the separation of the mitochondrial from the nuclear genome by great distances. Neuronal activity dictates COX activity that reflects protein amount, which, in turn, is regulated at the transcriptional level. All 13 COX transcripts are up- and downregulated by neuronal activity. The ten nuclear COX transcripts and those for Tfam and Tfbms important for mitochondrial COX transcripts are transcribed in the same transcription factory. Bigenomic regulation of all 13 transcripts is mediated by nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2). NRF-1, in addition, also regulates critical neurochemicals of glutamatergic synaptic transmission, thereby ensuring the tight coupling of energy metabolism and neuronal activity at the molecular level in neurons.

Fig. 12.1

Schematic diagram depicting that PGC-1α coordinates the induction of NRF-1 and NRF-2 in regulating the transcription of all ten nuclear-encoded COX subunit genes, as well as the genes for Tfam, Tfb1m, and Tfb2m in the nucleus. Translation in the cytoplasm leads to the generation of the respective proteins, all of which enter into the mitochondria. Within the mitochondrion, the three mitochondrial-encoded COX genes are transcribed aided by the TFs and translated into polypeptides. Together, the nuclear- and mitochondrial-encoded COX subunits form the holoenzyme that is complex IV of the electron transport chain (ETC).

Fig. 12.2

Schematic rendition of a dynamic transcription factory in which the loops of 13 genomic loci for the ten nuclear-encoded COX subunit genes and genes for Tfam, Tfb1m, and Tfb2m are cotranscribed, with the aid of RNA polymerase II, NRF-1, NRF-2, and possibly other transcription factors and coactivators. (Reproduced with permission from Dhar et al 2009a).

Fig. 12.3

A Venn diagram illustrating the tight coupling between neuronal activity and energy metabolism at the molecular level by having the same transcription factor, NRF-1, coregulating genes for critical glutamatergic neurochemicals (Grin1, Grin2b, Gria2, Nos1, and NR2B motor Kif17) as well as all 13 subunits of COX. Such coupling ensures that energy production exquisitely matches energy demand of neuronal activity.