Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Adv Exp Med Biol. 2012;748:283-304. doi: 10.1007/978-1-4614-3573-0_12.
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.
细胞色素 c 氧化酶是线粒体电子传递链的末端酶，没有它，氧化代谢就无法完成。它是哺乳动物细胞中仅有的四个独特的双基因蛋白之一。全酶由三个线粒体编码和十个核编码亚基以 1:1 的化学计量组成。十个核亚基基因位于九个不同的染色体上。如此多亚基、多染色体、双基因酶的协调调节构成了一个挑战。对于神经元来说尤其如此，它们的线粒体广泛分布在广泛的树突和轴突过程中，导致线粒体与核基因组之间的分离距离很大。神经元活动决定了 COX 活性，反映了蛋白质的数量，而蛋白质的数量反过来又受到转录水平的调节。所有 13 个 COX 转录本都受到神经元活动的上调和下调。十个核 COX 转录本以及对线粒体 COX 转录本重要的 Tfam 和 Tfbms 转录本在同一个转录工厂中进行转录。所有 13 个转录本的双基因调节都由核呼吸因子 1 和 2（NRF-1 和 NRF-2）介导。NRF-1 还调节谷氨酸能突触传递的关键神经化学物质，从而确保在分子水平上在神经元中能量代谢和神经元活动的紧密偶联。
