Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II

Abstract

Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism.

Monitoring the Redox Status in Multiple Sclerosis

“…Superoxide (O 2 −• ) is produced by XO in the reperfusion phase of ischemia, LOX, COX, and NADPH-dependent oxidase [ 105 ]. In the endoplasmic reticulum NADH cytochrome b5 reductase can leak electrons to molecular oxygen (O 2 ) to generate superoxide (O 2 −• ) during the NADPH-dependent oxidation of xenobiotics [ 106 ].…”

New potential biomarker for stratification of patients for pharmacological vitamin C in adjuvant settings of cancer therapy

“…Asc • is an intermediate product from the oxidation of ascorbate by transition metal ions and/or free radicals. Asc • is a by-product of the conversion of methemoglobin to hemoglobin in erythrocytes, as well as of some enzymatic hydroxylation reactions [27,28]. NADH:cytochrome b5 oxidoreductase 3 (Cyb5R3) catalyzes rapid conversion of Asc • to ascorbate, using cytosolic NADH as an electron donor [4,14].…”

“…OMM Cyb5R3 uses a cytochrome b5-like hemoprotein of the outer mitochondrial membrane, which is distinct from microsomal cytochrome b5 [13]. Down-regulation and/or inhibition of OMM Cyb5R3 are accompanied by mitochondrial dysfunction, decrease of ATP production and NAD + /NADH ratio, and higher sensitivity to oxidative stress [27]. Hb – hemoglobin; Met-Hb – methemoglobin; Me – transition metal; OMM – outer mitochondrial membrane; R • – free radical; RH – non-radical product; S – substrate of enzymatic hydroxylation; SOH – product of enzymatic hydroxylation.…”

“…OMM Cyb5R3 uses a cytochrome b5-like hemoprotein of the outer mitochondrial membrane, which is distinct from microsomal cytochrome b5 [13]. Down-regulation and/or inhibition of OMM Cyb5R3 are accompanied by mitochondrial dysfunction, decrease of ATP production and NAD + /NADH ratio, and higher sensitivity to oxidative stress [27].…”

Monitoring the Redox Status in Multiple Sclerosis

“…Superoxide (O2 −• ) is produced by XO in the reperfusion phase of ischemia, LOX, COX, and NADPH-dependent oxidase[69]. In the endoplasmic reticulum NADH cytochrome b5 reductase can leak electrons to molecular oxygen (O2) to generate superoxide (O2 −• ) during the NADPH-dependent oxidation of xenobiotics[70].Most enzymes in the peroxisomes produce ROS during the catalysis of fatty acid α-and βoxidation, amino acid and glyoxylate metabolism, and synthesis of lipidic compounds. A large fraction of hydrogen peroxide (H2O2) generated inside peroxisomes was observed to penetrate the peroxisomal membrane and diffuse to the surrounding media [71].…”