Unlike glial cells that can fare quite well under anaerobic condition, neurons are dependent almost entirely on oxidative metabolism for their function and survival. Neurons are ideal cells for investigating the regulation of COX. The mechanism of regulating such a complex, multisubunit, bigenomic enzyme appears daunting and poorly understood until recent years, when the regulatory machinery was beginning to be revealed.ġ2.2 Cytochrome c Oxidase as a Metabolic Marker for Neurons To form a functional holoenzyme, precise coordination between the two genomes is necessary. The largest three subunits (COX I, II, III) are encoded in the maternally inherited mitochondrial genome, and the remaining ten (COX IV, Va,b, VIa,b,c, VIIa,b,c, and VIII) are nuclear-encoded in nine different chromosomes. COX holoenzyme has 13 subunits with 1:1 stoichiometry ( Kadenbach et al 1983). This implies that a) the mitochondrial genome retains its control of key subunits of the electron transport chain through evolution and b) the two genomes have to work closely together to ensure proper functioning of the oxidative phosphorylation machinery. It is one of only 4 bigenomic proteins in mammalian cells: complexes I, III, IV, and V of the electron transport chain, each of which has subunits from either the nuclear or the mitochondrial genome, and none of which is encoded entirely by a single genome. Thus, highly oxidative organs such as the heart, liver, kidney, skeletal muscles, and especially the brain, are critically dependent on COX for their normal functioning and survival.ĬOX is one of the most ancient enzymes known, parts of it evolved more than a billion years ago. Inactivation of COX by cyanide, azide, or carbon monoxide is incompatible with life, as oxidative metabolism cannot be carried to completion, and no ATP can be generated from mitochondria. It assists in the pumping of protons from the matrical to the cytosolic side of the inner mitochondrial membrane, setting up the electrochemical proton gradient that drives the synthesis of ATP from ADP and phosphate by ATP synthase (complex V). It catalyzes the oxidation of its substrate, cytochrome c, and the reduction of molecular oxygen to water. 1.9.3.1) is the terminal enzyme of the mitochondrial electron transport chain. 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.Ĭytochrome c oxidase (COX, cytochrome aa3, ferrocytochrome c oxygen oxidoreductase, complex IV, E.C. Bigenomic regulation of all 13 transcripts is mediated by nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2). The ten nuclear COX transcripts and those for Tfam and Tfbms important for mitochondrial COX transcripts are transcribed in the same transcription factory. All 13 COX transcripts are up- and downregulated by neuronal activity. Neuronal activity dictates COX activity that reflects protein amount, which, in turn, is regulated at the transcriptional level. It is especially so for neurons, whose mitochondria are widely distributed in extensive dendritic and axonal processes, resulting in the separation of the mitochondria from the nuclear genome by great distances. The coordinated regulation of such a multisubunit, multichromosomal, bigenomic enzyme poses a challenge. The ten nuclear subunit genes are located in nine different chromosomes. The holoenzyme is made up of three mitochondrial-encoded and ten nuclear-encoded subunits in a 1:1 stoichiometry. It is one of only four unique, bigenomic proteins in mammalian cells. Cytochrome c oxidase is the terminal enzyme of the mitochondrial electron transport chain, without which oxidative metabolism cannot be carried to completion.
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