Mitochondrial- and nuclear-encoded subunits of cytochrome oxidase in neurons: Differences in compartmental distribution, correlation with enzyme activity, and regulation by neuronal activity

Abstract

Cytochrome oxidase (CO), a mitochondrial energy-generating enzyme, contains both mitochondrial- and nuclear-encoded subunits. In neurons, local levels of CO activity vary among different neuronal compartments, reflecting local demands for energy. The goals of the present study were to determine if compartmental distribution of CO subunit proteins from the two genomes was correlated with local CO activity, and if their expression was regulated proportionately in neurons. The subcellular distributions of mitochondrial-encoded CO III and nuclear-encoded CO Vb proteins were quantitatively analyzed in mouse cerebellar sections subjected to postembedding immunocytochemistry. Local levels of subunit proteins were also compared to local CO activity, as revealed by CO cytochemistry. In order to study the regulation of subunit protein expression, we assessed changes in immunoreactivity of the two CO subunits as well as changes in CO activity in mouse superior colliculus after 1 to 7 days of monocular enucleation. We found that immunoreaction product for both CO III and CO Vb existed almost exclusively in mitochondria, but their compartmental distributions were different. CO III was nonhomogeneously distributed among different neuronal compartments, where its local level was positively correlated with that of CO activity. In contrast, the subcellular distribution of CO Vb was relatively uniform and did not bear a direct relationship with that of CO activity. Moreover, the two subunit proteins were disproportionately regulated by neuronal activity. CO III and CO activity exhibited parallel decreases after the deprivation of afferent input, and their changes were earlier and to a greater degree than that of CO Vb proteins. Thus, the present findings indicate that the local expression and/or distribution of CO subunit proteins from the two genomes may involve different regulatory mechanisms in neurons. Our data also suggest that the activity-dependent regulation of mitochondrial-encoded CO subunits is likely to play a major role in controlling the local levels of CO content and its activity.

Transcriptional coupling of synaptic transmission and energy metabolism: Role of nuclear respiratory factor 1 in co-regulating neuronal nitric oxide synthase and cytochrome c oxidase genes in neurons

“…The level of COX activity in the normal monkey retina, monkey visual cortex, and cultured rat primary neurons are positively correlated with the density of distribution of excitatory neurotransmitters and their receptors, such as glutamate, NMDA receptor subunit NR1, and NOS1 [11–12,46–49]. This is consistent with the fact that repolarization after excitation-induced depolarization is highly energy-dependent and consumes the bulk of ATP produced in the CNS [8].…”

Coupling of Energy Metabolism and Synaptic Transmission at the Transcriptional Level: Role of Nuclear Respiratory Factor 1 in Regulating both CytochromecOxidase and NMDA Glutamate Receptor Subunit Genes

“…Previously, we found that the level of COX activity in rat primary neuronal cultures, monkey retina, and monkey visual cortex under normal conditions are positively correlated with the intensity of distribution of excitatory neurotransmitters and their receptors, such as glutamate and NMDA receptor subunit NR1 (Nie and Wong-Riley, 1996;Wong-Riley et al, 1998a,b; Zhang and Wong-Riley, 2000b). This is consistent with the fact that repolarization after excitation-induced depolarization is highly energy-dependent and consumes the bulk of ATP produced in the CNS (Wong-Riley, 1989).…”

Replication and Transcription of Mammalian Mitochondrial Dna

“…Finally, there is evidence suggesting the existence of mechanisms for local regulation of mitochondrial biogenesis, in particular cell domains in neurons (Hevner & Wong-Riley, 1993;Nie & Wong-Riley, 1996) and of a direct response of the mitochondrial transcription apparatus to external signals in the absence of nuclear gene expression (Gaines et al 1987;Enriquez et al 1996Enriquez et al , 1999a.…”