Abstract
Cytochrome b5 reductase (Cb5R) and cytochrome b5 (Cb5) are coupled redox systems with a high potential as biomarkers of health and disease in the brain because they regulate metabolic pathways that are essential to maintain normal neuronal function, like lipid biosynthesis, steroid and xenobiotics metabolism, neuronal bioenergetics and production of reactive oxygen species. Mutations of the Cb5R reported in humans produce recessive congenital methemoglobinemia of type II, a disease with severe clinical neurological dysfunctions. The isoform 3 of Cb5R (Cb5R3) and Cb5 are highly expressed in pyramidal neurons of the primary and secondary motor areas of frontoparietal cerebral cortex, hippocampus, vestibular, reticular and motor nuclei of the cerebellum and brain stem, and also in Purkinje and granule neurons of the cerebellum cortex. These brain areas are highly prone to undergo oxidative stress-induced neurodegeneration and their functional impairment can account for neurological deficits reported in type II congenital methemoglobinemia.
Highlights
Productive superoxide anion and its dismutation metabolite hydrogen peroxide[4]
As an impaired neuronal bioenergetics is a metabolic alteration shared in many neurodegenerative diseases, it is of interest to recall here that the NADH oxidase activity of the Cytochrome b5 reductase (Cb5R) bound to the external mitochondrial membrane has been proposed to contribute in the maintenance of adequate levels of cellular ATP, via direct reduction of cytochrome c through an electron shuttle with cytochrome c oxidase[9]
Because extracellular ascorbate is a major antioxidant defense in the brain, in previous works we have shown the presence of ascorbate-free radical reductase activity in synaptic membranes[13] and the association of Cb5R with the plasma membrane in cerebellar granule neurons in culture[14,15,16]
Summary
Productive superoxide anion and its dismutation metabolite hydrogen peroxide[4]. Taking into account the relevance of endoplasmic reticulum stress in Alzheimer’s disease[6,7], it is to be noted that the Cb5R isoform 4 (Cb5R4) - a flavohemeprotein containing Cb5 and Cb5R domainshas been shown to protect against endoplasmic reticulum stress-induced lipotoxicity[8]. Cb5 is a pleiotropic co-factor of multiple enzymes and redox chains that play critical roles for normal function of healthy mammalian organisms, and it is largely reduced by the NADH-dependent Cb5R activity (reviewed in Samhan-Arias and Gutierrez-Merino[1]).
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