Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress

Logan, Suzanna; Yin, Liya; Geldenhuys, Werner J.; Enrick, Molly; Stevanov, Kelly; Carroll, Richard T.; Ohanyan, Vahagn; Kolz, Christopher; Chilian, William M.

doi:10.1007/s00395-015-0471-z

Cited by 20 publications

(20 citation statements)

References 36 publications

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“…Several studies investigated the impact of mitoNEET in disease models, which are associated with oxidative stress like obesity [ 13 ], cancer [ 14 ] and inflammation-induced Parkinson`s disease [ 15 ]. Recently the novel thiazolidinedione mitoNEET ligand-1 has been reported to show a protective effect on cardiac stem cell survival under oxidative stress conditions [ 35 ]. However, the role of mitoNEET during myocardial ischemia and reperfusion injury, which is also related to increased oxidative stress has not been characterized yet.…”

Section: Discussionmentioning

confidence: 99%

MitoNEET Protects HL-1 Cardiomyocytes from Oxidative Stress Mediated Apoptosis in an In Vitro Model of Hypoxia and Reoxygenation

et al. 2016

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The iron-sulfur cluster containing protein mitoNEET is known to modulate the oxidative capacity of cardiac mitochondria but its function during myocardial reperfusion injury after transient ischemia is unknown. The purpose of this study was to analyze the impact of mitoNEET on oxidative stress induced cell death and its relation to the glutathione-redox system in cardiomyocytes in an in vitro model of hypoxia and reoxygenation (H/R). Our results show that siRNA knockdown (KD) of mitoNEET caused an 1.9-fold increase in H/R induced apoptosis compared to H/R control while overexpression of mitoNEET caused a 53% decrease in apoptosis. Necrosis was not affected. Apoptosis of both, mitoNEET-KD and control cells was diminished to comparable levels by using the antioxidants Tiron and glutathione compound glutathione reduced ethyl ester (GSH-MEE), indicating that mitoNEET-dependent apoptosis is mediated by oxidative stress. The interplay between mitoNEET and glutathione redox system was assessed by treating cardiomyocytes with 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthio-carbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), known to effectively inhibit glutathione reductase (GSR) and to decrease the GSH/GSSG ratio. Surprisingly, inhibition of GSR-activity to 20% by 2-AAPA decreased apoptosis of control and mitoNEET-KD cells to 23% and 25% respectively, while at the same time mitoNEET-protein was increased 4-fold. This effect on mitoNEET-protein was not accessible by mitoNEET-KD but was reversed by GSH-MEE. In conclusion we show that mitoNEET protects cardiomyocytes from oxidative stress-induced apoptosis during H/R. Inhibition of GSH-recycling, GSR-activity by 2-AAPA increased mitoNEET-protein, accompanied by reduced apoptosis. Addition of GSH reversed these effects suggesting that mitoNEET can in part compensate for imbalances in the antioxidative glutathione-system and therefore could serve as a potential therapeutic approach for the oxidatively stressed myocardium.

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Section: Discussionmentioning

confidence: 99%

MitoNEET Protects HL-1 Cardiomyocytes from Oxidative Stress Mediated Apoptosis in an In Vitro Model of Hypoxia and Reoxygenation

et al. 2016

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“…Global mNTKO mice were obtained from Taconic Laboratories, and were kindly provided by Dr. Werner J. Geldenhuys (Northeast Ohio Medical University) (57). mNTKO mice on C57BL/6 background were viable and phenotypically normal under a chow diet.…”

Section: Methodsmentioning

confidence: 99%

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

Jogasuria

Wang

et al. 2016

Journal of Biological Chemistry

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MitoNEET (mNT) (CDGSH iron-sulfur domain-containing protein 1 or CISD1) is an outer mitochondrial membrane protein that donates 2Fe-2S clusters to apo-acceptor proteins. In the present study, using a global mNT knock-out (mNTKO) mouse model, we investigated the in vivo functional role of mNT in the development of alcoholic steatohepatitis. Experimental alcoholic steatohepatitis was achieved by pair feeding wild-type (WT) and mNTKO mice with Lieber-DeCarli ethanol-containing diets for 4 weeks. Strikingly, chronically ethanol-fed mNTKO mice were completely resistant to ethanolinduced steatohepatitis as revealed by dramatically reduced hepatic triglycerides, decreased hepatic cholesterol level, diminished liver inflammatory response, and normalized serum ALT levels. Mechanistic studies demonstrated that ethanol administration to mNTKO mice induced two pivotal endocrine hormones, namely, adipose-derived adiponectin and gut-derived fibroblast growth factor 15 (Fgf15). The elevation in circulating levels of adiponectin and Fgf15 led to normalized hepatic and serum levels of bile acids, limited hepatic accumulation of toxic bile, attenuated inflammation, and amelioration of liver injury in the ethanol-fed mNTKO mice. Other potential mechanisms such as reduced oxidative stress, activated Sirt1 signaling, and diminished NF-B activity also contribute to hepatic improvement in the ethanol-fed mNTKO mice. In conclusion, the present study identified adiponectin and Fgf15 as pivotal adipose-gut-liver metabolic coordinators in mediating the protective action of mNT deficiency against development of alcoholic steatohepatitis in mice. Our findings may help to establish mNT as a novel therapeutic target and pharmacological inhibition of mNT may be beneficial for the prevention and treatment of human alcoholic steatohepatitis.NEET proteins (mitoNEET (CISD1, mNT), 3 nutrient-deprivation autophagy factor-1 (NAF-1; CISD2), and Miner 2 (CISD3)) are a class of redox active iron-sulfur (2Fe-2S) proteins (1, 2). Among the three NEET family members, mNT encoded by the CISD1 gene is the founding member of the NEET family, and it is localized in the outer mitochondrial membrane and regulates the maturation and shuttling of 2Fe-2S clusters. mNT has been identified as a mitochondrial target of the anti-diabetic thiazolidinedione drugs (3, 4). Thiazolidinediones such as pioglitazone are capable of binding and stabilizing the mNT protein against 2Fe-2S cluster release, and thus, protecting tissue from mitochondrial injury (4). NAF-1 encoded by CISD2 is closely related to mNT, sharing 44% overall sequence identity and highly similar structure and functions (1, 5). However, the functions of CISD3 are not well understood.Increasing evidences have revealed that mNT is an important regulator of diverse biological processes, including mitochondrial function, iron metabolism, reactive oxygen species (ROS) homeostasis, lipid metabolism, inflammation process, and autophagy (1-4, 6 -15). Utilizing gain and loss of function mouse models, studies have demo...

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“…In beta cells, increased expression of mitoNEET leads to hyperglycemia and glucose intolerance [4]. Misregulation of mitoNEET expression has also been attributed to the development of neurodegenerative disease [5, 6] and cardiovascular disease [7], breast cancer proliferation [8–10], browning of white adipose tissue [11], among other pathological conditions [12]. It has thus been proposed that mitoNEET is a key regulator for energy metabolism, iron homeostasis, and production of reactive oxygen species in mitochondria [13].…”

Section: Introductionmentioning

confidence: 99%

Flavin nucleotides act as electron shuttles mediating reduction of the [2Fe-2S] clusters in mitochondrial outer membrane protein mitoNEET

Landry

Wang

Cheng

et al. 2017

Free Radical Biology and Medicine

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MitoNEET, a primary target of type II diabetes drug pioglitazone, has an essential role in regulating energy metabolism, iron homeostasis, and production of reactive oxygen species in mitochondria. Structurally, mitoNEET is anchored to the mitochondrial outer membrane via its N-terminal transmembrane α-helix. The C-terminal cytosolic domain of mitoNEET hosts a redox active [2Fe-2S] cluster via three cysteine and one histidine residues. Here we report that the reduced flavin nucleotides can rapidly reduce the mitoNEET [2Fe-2S] clusters under anaerobic or aerobic conditions. In the presence of NADH and flavin reductase, about 1 molecule of flavin nucleotide is sufficient to reduce 100 molecules of the mitoNEET [2Fe-2S] clusters in 4 minutes under aerobic conditions. The electron paramagnetic resonance (EPR) measurements show that flavin mononucleotide (FMN), but not flavin adenine dinucleotide (FAD), has a specific interaction with mitoNEET. Molecular docking models further reveal that flavin mononucleotide binds mitoNEET at the region between the N-terminal transmembrane α-helix and the [2Fe-2S] cluster binding domain. The closest distance between the [2Fe-2S] cluster and the bound flavin mononucleotide in mitoNEET is about 10 Å, which may facilitate rapid electron transfer from the reduced flavin nucleotide to the [2Fe-2S] cluster in mitoNEET. The results suggest that flavin nucleotides may act as electron shuttles to reduce the mitoNEET [2Fe-2S] clusters and regulate mitochondrial functions in human cells.

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Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress

Cited by 20 publications

References 36 publications

MitoNEET Protects HL-1 Cardiomyocytes from Oxidative Stress Mediated Apoptosis in an In Vitro Model of Hypoxia and Reoxygenation

MitoNEET Protects HL-1 Cardiomyocytes from Oxidative Stress Mediated Apoptosis in an In Vitro Model of Hypoxia and Reoxygenation

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

Flavin nucleotides act as electron shuttles mediating reduction of the [2Fe-2S] clusters in mitochondrial outer membrane protein mitoNEET

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