Cytochrome c Oxidase and Its Role in Neurodegeneration and Neuroprotection

Abstract

A hallmark of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and stroke is a malfunction of mitochondria including cytochrome c oxidase (COX), the terminal enzyme complex of the respiratory chain. COX is ascribed a key role based on mainly two regulatory mechanisms. These are the expression of isoforms and the binding of specific allosteric factors to nucleus--encoded subunits. These characteristics represent a unique feature of COX compared with the other respiratory chain complexes. Additional regulatory mechanisms, such as posttranslational modification, substrate availability, and allosteric feedback inhibition by products of the COX reaction, control the enzyme activity in a complex way. In many tissues and cell types, COX represents the rate-limiting enzyme of the respiratory chain which further emphasizes the impact of the regulation of COX as a central site for regulating energy metabolism and oxidative stress. Two of the best-analyzed regulatory mechanisms of COX to date are the allosteric feedback inhibition of the enzyme by its indirect product ATP and the expression of COX subunit IV isoforms. This ATP feedback inhibition of COX requires the expression of COX isoform IV-1. At high ATP/ADP ratios, ADP is exchanged for ATP at the matrix side of COX IV-1 leading to an inhibition of COX activity, thus enabling COX to sense the energy level and to adjust ATP synthesis to energy demand. However, under hypoxic, toxic, and degenerative conditions, COX isoform IV-2 expression is up-regulated and exchanged for COX IV-1 in the enzyme complex. This COX IV isoform switch causes an abolition of the allosteric ATP feedback inhibition of COX and consequently the loss of sensing the energy level. Thus, COX activity is increased leading to higher levels of ATP in neural cells independently of the cellular energy level. Concomitantly, ROS production is increased. Thus, under pathological conditions, neural cells are provided with ATP to meet the energy demand, but at the expense of elevated oxidative stress. This mechanism explains the functional relevance of COX subunit IV isoform expression for cellular energy sensing, ATP production, and oxidative stress levels. This, in turn, affects neural cell function, signaling, and -survival. Thus, COX is a crucial factor in etiology, progression, and prevalence of numerous human neurodegenerative diseases and represents an important target for developing diagnostic and therapeutic tools against those diseases.

Essential Roles of Neutral Ceramidase and Sphingosine in Mitochondrial Dysfunction Due to Traumatic Brain Injury

“…The present study implicates another sphingolipid, sphingosine, as a critical determinant regulating the activity of the respiratory chain rate-limiting enzyme COX. There are two well known regulatory mechanisms of COX: the allosteric feedback inhibition of the enzyme by its direct product ATP and the expression of COX subunits (62). These studies suggest a novel mechanism of regulation of COX activity by sphingolipid sphingosine and identify the metabolic pathway involved in generation and utilization of sphingosine in mitochondria.…”

“…Inactivation of COX by inhibitors, such as cyanide and carbon monoxide, is incompatible with life. In the brain and some other highly oxidative organs, such as the heart, liver, and kidney, COX represents the rate-limiting enzyme of the respiratory chain, which emphasizes the impact of regulating COX as a central site for the regulation of the energy metabolism (62).…”

Neuroprotective Effect of Insulin-like Growth Factor-II on 1- Methyl-4-Phenyl Pyridinium-Induced Oxidative Damage in Cortical Neuronal Cells

“…The elevated level of TBARS and LOOH was decreased to near control levels. To assess mitochondrial function, oxidative phosphorylation was evaluated by measuring the MMP [22] and mitochondrial cytochrome-c oxidase activity, which is the rate-limiting step of the mitochondrial respiratory chain [23]. JC-1 fluorescence was measured which reflects the average MMP of all mitochondria inside the cells.…”

Regulation and Quantification of Cellular Mitochondrial Morphology and Content

“…phosphorylation, (de)acylation, oxidative modification) and/or expression regulation of only a subset of mitochondrial proteins (e.g. [57][58][59]). In case of genetic mitochondrial disorders, increased mitochondrial biogenesis in skeletal muscle can be diagnostically observed as "ragged red fibres" [60].…”