Brain Cytochrome Oxidase

Abstract

Cytochrome oxidase is a ubiquitous housekeeping enzyme that holds one of the important keys to life. As a major oxidative enzyme and an energy-generating enzyme, cytochrome oxidase serves as a reliable indicator of neurons’ oxidative capacity and energy metabolism. The tight coupling between energy metabolism and neuronal activity further enables cytochrome oxidase to serve as a sensitive metabolic marker for neuronal functional activity, which includes firing rates of neurons and slow depolarizing potentials occurring primarily in dendrites. In the past two decades, much has been learned about the heterogeneous distribution of cytochrome oxidase in neurons at the regional, laminar, cellular and subcellular levels. The local activity of cytochrome oxidase is correlated with the physiological activity of each area, cell, or subcellular compartment. Regions of high cytochrome oxidase activity are dominated by excitatory, glutamatergic synapses. Changes in the physiological activity of neurons can induce parallel changes in the activity of cytochrome oxidase in developing and adult systems. Cytochrome oxidase activity is controlled mainly by regulation of protein amount, which is regulated transcriptionally. Being bigenomically encoded, cytochrome oxidase is under complex interactive regulation of both mitochondrial and nuclear gene expression. Cytochrome oxidase subunit complementary DNAs were isolated from a murine complementary DNA library, cloned and sequenced. Transcripts from the two genomes have distinct subcellular as well as compartmental distributions suggestive of different regulatory mechanisms. Antibodies generated against subunit proteins from the two genomes also showed differential distributions among neuronal compartments. Nuclear-encoded subunits are translated exclusively in the cell bodies and are delivered intramitochondrially to distal processes. A precursor pool exists in dendrites, where further processing of nuclear-encoded subunits and holoenzyme assembly are presumably governed by local energy demands. Under normal and functionally altered states, cytochrome oxidase activity is linked more closely to transcripts and subunit proteins derived from mitochondrial than from nuclear sources. This indicates that local cytochrome oxidase activity in neurons is controlled mainly by regulation of the mitochondrial genes that encode the catalytic subunits of the enzyme.