CYB5R3: a key player in aerobic metabolism and aging?

Aging results from a complex and not completely understood chain of processes that are associated with various negative metabolic consequences and ultimately leads to senescence and death. The intracellular ratio of pyridine nucleotides (NAD+/NADH), has been proposed to be at the center stage of age-related biochemical changes in organisms, and may help to explain the observed influence of calorie restriction and energy-sensitive proteins on lifespan in model organisms. Indeed, the NAD+/NADH ratios affect the activity of a number of proteins, including sirtuins, which have gained prominence in the aging field as potential mediators of the beneficial effects of calorie restriction and mediating lifespan. Here we review the activities of a redox enzyme (NQR1 in yeast and CYB5R3 in mammals) that also influences the NAD+/NADH ratio and may play a regulatory role that connects aerobic metabolism with aging

Cell Survival from Chemotherapy Depends on NF-κB Transcriptional Up-Regulation of Coenzyme Q Biosynthesis

9 pages and 6 figures.[Background] Coenzyme Q (CoQ) is a lipophilic antioxidant that is synthesized by a mitochondrial complex integrated by at least ten nuclear encoded COQ gene products. CoQ increases cell survival under different stress conditions, including mitochondrial DNA (mtDNA) depletion and treatment with cancer drugs such as camptothecin (CPT). We have previously demonstrated that CPT induces CoQ biosynthesis in mammal cells.[Methodology/Principal Findings] CPT activates NF-κB that binds specifically to two κB binding sites present in the 5′-flanking region of the COQ7 gene. This binding is functional and induces both the COQ7 expression and CoQ biosynthesis. The inhibition of NF-κB activation increases cell death and decreases both, CoQ levels and COQ7 expression induced by CPT. In addition, using a cell line expressing very low of NF-κB, we demonstrate that CPT was incapable of enhancing enhance both CoQ biosynthesis and COQ7 expression in these cells.[Conclusions/Significance] We demonstrate here, for the first time, that a transcriptional mechanism mediated by NF-κB regulates CoQ biosynthesis. This finding contributes new data for the understanding of the regulation of the CoQ biosynthesis pathway.This work was supported by spanish Ministerio de Educacion y Ciencia Grant BFU2005-03017.Peer reviewe

Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II

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

Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II

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.This work has been funded by the Instituto de Salud Carlos III FIS PI17-01286 grant. Authors were also funded by the Andalusian Government BIO177 research group

Antioxidanst in differentiation of leukemic cells

38 páginas, 3 figuras, 1 tabla. Editor: Hitoshi Saitama.The therapy of leukaemia based on the use of compounds able to reinitiate the differentiation program has been extensively studied. The use of calcitriol (1,25D3) or trans-retinoic acid (ATRA) in myeloid or monocytic leukemic cell differentiation has been also clinically taken into consideration. Both are natural compounds accepted at relatively high doses by the organism, however, several other secondary effects take place because their other respective main functions different than regulating the differentiation program in cancerous cells. To avoid the secondary effects due to overloading of both, ATRA or 1,25D3, therapies based on the co-administration of other natural compounds such as vitamin C, vitamin E, polyphenols, caretonoids or other antioxidants acting as anti-cancer active compounds have been taking into consideration. In several cases, these natural compounds do not affect by themselves the differentiation program in leukemic cells but they are able to enhance the effect of the differentiation-active compounds such as ATRA or 1,25D3. The present chapter reviews the effect of the combination of these natural antioxidant compounds on the treatment of leukemic cells and will try to define the probable common mechanism of action for this plethora of substances.Peer reviewe

Coenzyme Q biosynthesis is regulated by RNA-protein interaction

Resumen del póster presentado al 22nd IUBMB & 37th FEBS Congress, celebrado en Sevilla (España) del 4 al 9 de septiembre de 2012.-- et al.Coenzyme Q (CoQ) deficiency is a rare disorder with a variable phenotypic presentation that includes pure myopathy, myopathy with encephalopathy, cerebellar atrophy with ataxia, and infantile multisystem disease including encephalopathy and nephrophaty, and nephritic syndrome. Primary CoQ deficiency arises from mutations in COQ genes, while secondary forms of CoQ deficiency are caused by mutations in genes not involved in CoQ biosynthesis. In most patients, the exact site and nature of the defects on biosynthesis have not yet been identified. Because CoQ biosynthesis is complex and not fully defined, identification of the molecular genetic defects has been challenging. At least ten genes (COQ1-COQ10) forming a multi-peptide complex are required for CoQ biosynthesis. One of them, COQ7, is a central regulator of the pathway. We have previously demonstrated that NF-kB regulatesCOQ7 gene transcription under oxidative stress. Our current studies have uncovered the interaction of the RNAbinding protein (RBP) HuR and other as-yet unidentified RBPs with the 3'UTR region of the COQ7 mRNA. We propose a model of post-transcriptional regulation of COQ7 expression, whereby RBPs binding to the COQ7 3'UTR can rapidly and effectively alter COQ7 expression levels to adapt to changing cellular needs for cellular CoQ activity.Peer reviewe

The two faces of a same function: pro- and antiapoptotic role of ubiquinone

35 páginas, 7 figuras, 2 tablas. Scott R. Erlich (editor)Ubiquinone or coenzyme Q is an essential lipid present in almost all the cell membranes. It is a redox molecule able to accept and donate electrons to several other cellular components. This redox capability is key in the two main functions of ubiquinone in cells, an intermediate in the mitochondrial respiratory chain and the main lipidic antioxidant in cell membranes. During the last years, several works have confirmed the essential role of ubiquinone in life and death of cells. Several evidences indicate that ubiquinone is involved in cell defence against oxidative damage of membranes and particularly plasma membrane. Serum withdrawal increases lipid hydroperoxide levels resulting in a neutral sphingomyelinase-mediated apoptosis. Ubiquinone inhibits neutral sphingomyelinase activation preventing ceramide-dependen apoptosis. The cell population is based on the equilibrium between proliferation and cell death. The activation of cell growth factors leads to an increase of proliferation by activation of transduction signals, which activate/repress transcription factors involved on regulation of either anti- or pro-apoptotic genes. Multiple forms of tumor exhibit abnormal constitutive activation of phosphatidylinositol 3-kinase/Akt pathway, which is activated by several growth factors and constitutes a mechanism of tumor cells survival. Current evidence in our group support that biosynthesis of ubiquinone can be regulated by survival signal such as Akt or inhibitor kappa-B kinase path ways through of Nuclear Factor kappa-B and/or Forkhead Box Class O, a critical factor in the regulation of cell cycle arrest, apoptosis, and resistance to oxidate stress. Recent research has demonstrated that cells respond to chemotherapic agents by increasing ubiquinone levels, probably in an attempt of protect themselves from reactive oxygen species production. In addition, ubiquinone seems to be an important agent in the prevention of cell damage during aging as suggested by its increase in plasma membrane of caloric restricted animals. However, mitochondrial reduced and semireduced ubiquinone species are also a source of oxygen radicals that could promote molecular damage and apoptosis. Also, the insertion of foreign forms of ubiquinone to mitochondrial membranes induces higher levels of reactive oxygen species in cells and tissues. We show here a wide review of the two faces of a same function, the transfer of electrons by ubiquinone. Pro- and antiapoptotic cell mechanisms are dependent on this essential lipidic factor.Peer reviewe