Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Shulga, Nataly; Pastorino, John G.

doi:10.1242/jcs.140764

Cited by 19 publications

(17 citation statements)

References 54 publications

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“…However, this effect was reversed by the pretreatment of the cells with an anti-diabetes agent (pioglitazone) [40]. Taken together, our findings have demonstrated that the combination of alcohol and fructose is able to trigger hepatic IR and diabetes, as well as liver dysfunction in the absence of an increased BW, mostly via synergistic interaction.…”

Section: Discussionmentioning

confidence: 53%

Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

Alwahsh¹,

Xu²,

Schultze³

et al. 2014

PLoS ONE

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Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and insulin resistance-accompanied liver damage.

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Section: Discussionmentioning

confidence: 53%

Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

Alwahsh¹,

Xu²,

Schultze³

et al. 2014

PLoS ONE

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“…Many scientists have investigated the regulatory mechanism of necroptosis. Many different molecules were considered to participate in the occurrence and regulation of necroptosis, such as HtrA2/Omi, ubiquitin C-terminal hydrolase (UCH-L1) [ 36 ], CDGSH iron-sulfur domain-containing protein 1 (CISD1) [ 37 ], and calpain [ 38 ]. Of the numerous pathways investigated for their involvement in necroptosis, the RIP signaling pathway was the one that was first studied and gained the most attention.…”

Section: Discussionmentioning

confidence: 99%

Receptor interacting protein 3-induced RGC-5 cell necroptosis following oxygen glucose deprivation

et al. 2015

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BackgroundNecroptosis is a type of regulated form of cell death that has been implicated in the pathogenesis of various diseases. Receptor-interacting protein 3 (RIP3), a member of the RIP family of proteins, has been reported as an important necroptotic pathway mediator in regulating a variety of human diseases, such as myocardial ischemia, inflammatory bowel disease, and ischemic brain injury. Our previous study showed that RIP3 was expressed in rat retinal ganglion cells (RGCs), where it was significantly upregulated during the early stage of acute high intraocular pressure. Furthermore, RIP3 expression was co-localized with propidium iodide (PI)-positive staining (necrotic cells). These results suggested that RIP3 up-regulation might be involved in the necrosis of injured RGCs. In this study, we aimed to reveal the possible involvement of RIP3 in oxygen glucose deprivation (OGD)-induced retinal ganglion cell-5 (RGC-5) necroptosis.MethodsRGC-5 cells were cultured in Dulbecco’s-modified essential medium and necroptosis was induced by 8 h OGD. PI staining and flow cytometry were performed to detect RGC-5 necrosis. RIP3 expression was detected by western blot and flow cytometry was used to detect the effect of RIP3 on RGC-5 necroptosis following OGD in rip3 knockdown cells. Malondialdehyde (MDA) lipid peroxidation assay was performed to determine the degree of oxidative stress.ResultsPI staining showed that necrosis was present in the early stage of OGD-induced RGC-5 cell death. The presence of RGC-5 necroptosis after OGD was detected by flow cytometry using necrostatin-1, a necroptosis inhibitor. Western blot demonstrated that RIP3 up-regulation may be involved in RGC-5 necroptosis. Flow cytometry revealed that the number of OGD-induced necrotic RGC-5 cells was reduced after rip3 knockdown. Furthermore, MDA levels in the normal RGC-5 cells were much higher than in the rip3-knockdown cells after OGD.ConclusionsOur findings suggest that RGC-5 cell necroptosis following OGD is mediated by a RIP3-induced increase in oxidative stress.

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“…Another recent study demonstrated the relationship between mNT and the inflammatory mediator TNF-α in liver cells [74]. Exposure of primary mouse hepatocytes to fructose and ethanol induced the overexpression of mNT, which primed the cells for TNF-α induced cytotoxicty.…”

Section: Mnt Is Involved In Inflammatory and Metabolic Diseasesmentioning

confidence: 92%

Structure–function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease

Tamir

Paddock

Darash-Yahana-Baram

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

135

230

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A novel family of 2Fe-2S proteins, the NEET family, was discovered during the last decade in numerous organisms, including archea, bacteria, algae, plant and human; suggesting an evolutionary-conserved function, potentially mediated by their CDGSH Iron-Sulfur Domain. In human, three NEET members encoded by the CISD1-3 genes were identified. The structures of CISD1 (mitoNEET, mNT), CISD2 (NAF-1), and the plant At-NEET uncovered a homodimer with a unique "NEET fold", as well as two distinct domains: a beta-cap and a 2Fe-2S cluster-binding domain. The 2Fe-2S clusters of NEET proteins were found to be coordinated by a novel 3Cys:1His structure that is relatively labile compared to other 2Fe-2S proteins and is the reason of the NEETs' clusters could be transferred to apo-acceptor protein(s) or mitochondria. Positioned at the protein surface, the NEET's 2Fe-2S's coordinating His is exposed to protonation upon changes in its environment, potentially suggesting a sensing function for this residue. Studies in different model systems demonstrated a role for NAF-1 and mNT in the regulation of cellular iron, calcium and ROS homeostasis, and uncovered a key role for NEET proteins in critical processes, such as cancer cell proliferation and tumor growth, lipid and glucose homeostasis in obesity and diabetes, control of autophagy, longevity in mice, and senescence in plants. Abnormal regulation of NEET proteins was consequently found to result in multiple health conditions, and aberrant splicing of NAF-1 was found to be a causative of the neurological genetic disorder Wolfram Syndrome 2. Here we review the discovery of NEET proteins, their structural, biochemical and biophysical characterization, and their most recent structure-function analyses. We additionally highlight future avenues of research focused on NEET proteins and propose an essential role for NEETs in health and disease. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.

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Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Cited by 19 publications

References 54 publications

Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

Receptor interacting protein 3-induced RGC-5 cell necroptosis following oxygen glucose deprivation

Structure–function analysis of NEET proteins uncovers their role as key regulators of iron and ROS homeostasis in health and disease

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