Natural mutations lead to enhanced proteasomal degradation of human Ncb5or, a novel flavoheme reductase

Lizák, Beáta; Nagy, Szilvia K.; Mészáros, Tamás; Zámbó, Veronika; Mandl, József; Csala, Miklós; Kereszturi, Éva

doi:10.1016/j.biochi.2013.03.004

Cited by 8 publications

(8 citation statements)

References 23 publications

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“…Samples were then centrifuged at 16,100 rcf for 10 minutes and 100 μL of the supernatant collected. Ten (10) μL of supernatant was then mixed well in a clear-bottom 96-well plate with 190 μL of chromogen solution, allowed to incubate for 10 minutes at room temperature, and the absorbance at 535 nm was determined using a Tecan Plate Reader. Chromogen solution consisted of 0.01% bathophenanthroline-disulfonic acid, 0.1% thioglycolic acid, and 7 M sodium acetate.…”

Section: Methodsmentioning

confidence: 99%

“…The cerebellum underwent dehydration processing and was embedded in paraffin wax for sectioning. Ten (10) μM sections were taken and placed on Superfrost Plus slide (Fisher, #12-550-15).…”

Section: Methodsmentioning

confidence: 99%

“…Naturally occurring polymorphism’s in human NCB5OR have been shown result in increased proteasomal degradation (10). Transgenic mice globally deficient in NCB5OR (GKO) have low birth weight (beginning at 2 weeks of age), petite skeletal structure/build, impaired lipid storage and lipoatrophy, hypermetabolism, mitochondrial dysfunction, and early-onset diabetes from necrotic beta cell loss when compared to normal or wild-type (WT) control mice (11–14).…”

Section: Introductionmentioning

confidence: 99%

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Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

et al. 2016

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Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. 59Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 weeks and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain.

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Section: Methodsmentioning

confidence: 99%

“…The cerebellum underwent dehydration processing and was embedded in paraffin wax for sectioning. Ten (10) μM sections were taken and placed on Superfrost Plus slide (Fisher, #12-550-15).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

et al. 2016

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“…In the latter case, no significant contribution has been assigned to mutations or variations within the diabetic population [65], yet Ncb5or null mice develop lean diabetes at age 7 weeks as a result of beta-cell demise and display gross mitochondrial morphological changes accompanied by altered lipid metabolism [64, 70, 75]. Interestingly, naturally occurring missense mutations in human Ncb5or lead to improper folding and significantly reduced levels of intracellular Ncb5or [76]. Our recent data also suggest that ablation of Ncb5or leads to iron dyshomeostasis [77].…”

Section: Forming the Mind Paradigm: Frataxin Ncb5or And The Monogenmentioning

confidence: 99%

Common defects of mitochondria and iron in neurodegeneration and diabetes (MIND): A paradigm worth exploring

Stroh¹,

Swerdlow²,

Zhu³

2014

Biochemical Pharmacology

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A popular, if not centric, approach to the study of an event is to first consider that of the simplest cause. When dissecting the underlying mechanisms governing idiopathic diseases, this generally takes the form of an ab initio genetic approach. To date, this genetic ‘smoking gun’ has remained elusive in diabetes mellitus and for many affected by neurodegenerative diseases. With no single gene, or even subset of genes, conclusively causative in all cases, other approaches to the etiology and treatment of these diseases seem reasonable, including the correlation of a systems’ predisposed sensitivity to particular influence. In the cases of diabetes mellitus and neurodegenerative diseases, overlapping themes of mitochondrial influence or dysfunction and iron dyshomeostasis are apparent and relatively consistent. This mini-review discusses the influence of mitochondrial function and iron homeostasis on diabetes mellitus and neurodegenerative disease, namely Alzheimer’s disease. Also discussed is the incidence of diabetes accompanied by neuropathy and neurodegeneration along with neurodegenerative disorders prone to development of diabetes. Mouse models containing multiple facets of this overlap are also described alongside current molecular trends attributed to both diseases. As a way of approaching the idiopathic and complex nature of these diseases we are proposing the consideration of a MIND (mitochondria, iron, neurodegeneration, and diabetes) paradigm in which systemic metabolic influence, iron homeostasis, and respective genetic backgrounds play a central role in the development of disease.

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“…This observation strongly supports the hypothesized functional link between SCD1 and Ncb5or [8] . Some natural human mutations of NCB5OR have been reported to remarkably decrease the level of active enzyme due to enhanced proteasomal degradation [28] ; therefore, the potential role of this gene in human pathology deserves further investigation.…”

mentioning

confidence: 99%

Lipotoxicity in the liver

Zámbó

Simon-Szabó

Szelényi

et al. 2013

WJH

Self Cite

157

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Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21 st century. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes, recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids, and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors, channels and transporters. However, it also induces endoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis. This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses. Key words: Saturated fatty acid; Lipotoxicity; Steatosis; Lipoapoptosis; Endoplasmic reticulum stress Core tip: Surplus of free fatty acids contributes to hepatic injuries in obesity and type 2 diabetes. Intracellular accumulation of fatty acyl-CoA causes oxidative and endoplasmic reticulum (ER) stress, which lead to cell death, inflammation and fibrosis. Steatohepatosis is the consequence of an intensive fat synthesis, aiming to reduce the metabolic burden. The higher toxicity of saturated vs unsaturated fatty acids is partly due to a limited capacity of the liver cells to insert them into triglycerides. Moreover, increased membrane saturation triggers the ER stress response though a unique mechanism, which aggravates the metabolic derangements and liver injuries.

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Natural mutations lead to enhanced proteasomal degradation of human Ncb5or, a novel flavoheme reductase

Cited by 8 publications

References 23 publications

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

Common defects of mitochondria and iron in neurodegeneration and diabetes (MIND): A paradigm worth exploring

Lipotoxicity in the liver

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