affect predominantly tissues with high energy demands (brain, heart, muscle). among the many classified mitochondrial diseases, those involving dysfunctional cox assembly are thought to be the most severe. the vast majority of cox disorders are linked to mutations in nuclear-encoded proteins referred to as assembly factors, or assembly proteins. these assembly factors contribute to cox structure and functionality, and are involved in several essential processes, including transcription and translation of mitochondrion-encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation. currently, mutations have been identified in seven cox assembly factors: surf1, sco1, sco2, cox10, cox15, cox20, coa5 and lrpprc. mutations in these proteins can result in altered functionality of sub-complex assembly, copper transport, or translational regulation. each gene mutation is associated with the etiology of a specific disease, with some having implications in multiple disorders. disorders involving dysfunctional cox assembly via gene mutations include leigh syndrome, cardiomyopathy, leukodystrophy, anemia, and sensorineural deafness. histochemistry the increased reliance of neurons on oxidative phosphorylation for energy facilitates the use of cox histochemistry in mapping regional brain metabolism in animals, since it establishes a direct and positive correlation between enzyme activity and neuronal activity. this can be seen in the correlation between cox enzyme amount and activity, which indicates the regulation of cox at the level of gene expression. cox distribution is inconsistent across different regions of the animal brain, but its pattern of its distribution is consistent across animals. this pattern has been observed in the monkey, mouse, and calf brain. one isozyme of cox has been consistently detected in histochemical analysis of the brain. such brain mapping has been accomplished in spontaneous mutant mice with cerebellar disease such as reeler and a transgenic model of alzheimer's disease. this technique has also been used to map learning activity in the animal brain. additional images etc complex iv