Metabolic syndrome and mitochondrial function: Molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function

Nicolson, Garth L.

doi:10.1002/jcb.21247

Cited by 86 publications

(96 citation statements)

References 162 publications

(213 reference statements)

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“…Accumulating evidence suggests that this indeed may be the case in diseases of the nervous system such as Parkinson's, Alzheimer's and Huntington's, and amyotrophic lateral sclerosis (for reviews, see Lin and Beal, 2006;Schapira, 2006;Whitton, 2007). Although it is likely that such a defect may occur in other conditions associated with inflammation, such as metabolic syndrome or diabetes mellitus, the evidence is at present contradictory (Mogensen et al, 2007;Boushel et al, 2007;Nicolson, 2007).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and HIF1α stabilization in inflammation

Garedew

Moncada

2008

Journal of Cell Science

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Activation of murine-derived J774.A1 macrophages with interferon γ and lipopolysaccharide leads to a progressive mitochondrial defect characterized by inhibition of oxygen consumption and a decrease in the generation of ATP by oxidative phosphorylation. These changes are dependent on the generation of nitric oxide (NO) by an inducible NO synthase that becomes a significant consumer of oxygen. Furthermore, in these activated cells there is a biphasic stabilization of the hypoxia-inducible factor HIF1α, the second phase of which is also dependent on the presence of NO. The mitochondrial defect and stabilization of HIF1α synergize to activate glycolysis, which, at its maximum, generates quantities of ATP greater than those produced by non-activated cells. Nevertheless, the amount of ATP generated is not sufficient to fulfil the energy requirements of the activated cells, probably leading to a progressive energy deficit with the consequent inhibition of cell proliferation and death.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and HIF1α stabilization in inflammation

Garedew

Moncada

2008

Journal of Cell Science

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“…We, as well as others, have previously suggested that elevated glucose levels can cause altered gene expression in vascular and islets cells (14)(15)(16)(17) (18). He also reported that these genes were differentially regulated by high (22 mM) compared to low glucose (5.5 mM) concentrations.…”

Section: Introductionmentioning

confidence: 62%

“…In 2005, Brownlee put forward a hypothesis linking these pathogenic mechanisms, explaining the overproduction of superoxide by the mitochondrial electron transport chain (23). For example, hyperglycemiainduced oxidative stress promotes the formation of advanced glycation end products, PKC activation, hexosamine and polyol pathway activity (18,24,25).…”

Section: Discussionmentioning

confidence: 99%

Identification of the novel protein FAM172A, and its up-regulation by high glucose in human aortic smooth muscle cells

Dong²,

Leong³

et al. 2010

Int J Mol Med

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Abstract. The family with sequence similarity 172, member A (FAM172A) is a hypothetical protein. We recently cloned the FAM172A gene from normal human aortic tissues. In a previous study we also showed that the FAM172A gene was up-regulated by high glucose levels in macrophages. In the present study, we further identified the FAM172A protein at the level of translation and studied the effects of high glucose levels on its expression in human aortic smooth muscle cells. The FAM172A gene was subcloned into the eukaryotic expression vectors, PDC315 and pEGFP-N2. The cloned sequence shows an open reading frame of 1251 nucleotides encoding a protein of 416 amino acids. We further expressed the recombinant FAM172A protein and generated rabbit anti-human FAM172A polyclonal antibodies. The FAM172A protein was identified for the first time at the translation level by Western blot analysis. Western blotting also demonstrated that the FAM172A protein could be detected in human aortic endothelial, human aortic smooth muscle cells and THP-1-derived macrophages, the highest expression being observed in the human aortic smooth muscle cells. By a combination of bioinformatics and confocal laser scanning microscopy, we found that the FAM172A protein in HEK293 cells, was mainly located in the nucleus, and that there was an Arb2 conserved domain in the FAM172A protein sequence. We also presented evidence that the FAM172 protein expression in human aortic smooth muscle cells was up-regulated by high glucose levels in a concentration-dependent and time-course manner. We speculated that as a novel protein, FAM172A could be involved in the pathogenesis of high glucose-induced vascular damage. IntroductionThe chronic complications of diabetes are generally divided into microvascular and macrovascular complications. The diabetic macrovascular disease or atherosclerosis and its complications, are the leading causes of morbidity and mortality in patients with type 2 diabetes mellitus (1,2). The histopathology of atherosclerosis in patients with diabetes is similar to that in patients without diabetes. However, compared to non-diabetic patients, atherosclerotic vascular damage in diabetic patients is more diffuse, more complicated and with clinically worse outcomes (3). Although insulin resistance, hypertension, dyslipidemia and other risk factors certainly contribute to the progression of diabetic macroangiopathy (3-8), the exact mechanisms of these pathological processes remain to be elucidated.Chronic hyperglycemia is a hallmark characteristic of diabetes and exerts its adverse effects on the cardiovascular system in many ways (7). There is universal agreement that hyperglycemia is a powerful and independent risk factor for diabetic cardiovascular complications (9-13). Therefore, hyperglycemia plays a crucial role in the pathogenesis of diabetic macrovascular complications.Glucose is one of the most important factors by which the expressions of genes in vascular or other cells are regulated. We, as well as others, have previously sugges...

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“…Since reactive oxygen species (ROS) produced by mitochondria are implicated in development of metabolic diseases (9,33), Prx3 may play a protective role in regulating adipocytes. The body weights of wild-type (WT) and Prx3 KO mice were indistinguishable at the 4-month period.…”

Section: Prx3 Ko Mice Display Larger Fat Pads With Hypertrophied Adipmentioning

confidence: 99%

“…However, histology showed that adipocytes were significantly larger in Prx3 KO mice. Hypertrophied adipocytes due to enlarged lipid droplets are frequently observed in mice models of obesity (17) and these cells exhibit impaired mitochondrial function and insulin signaling along with higher ROS levels (10,18,33).…”

Section: Fig 4 Protein Expression Profiles Of Adipocytes Obtained Fmentioning

confidence: 99%

Peroxiredoxin 3 Is a Key Molecule Regulating Adipocyte Oxidative Stress, Mitochondrial Biogenesis, and Adipokine Expression

Huh

Kim²,

Jeong³

et al. 2012

Antioxidants & Redox Signaling

139

108

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Aims: Increased oxidative stress and mitochondrial dysfunction in obese adipocytes contribute to adipokine dysregulation, inflammation, and insulin resistance. Results: Through an advanced proteomic analysis, we found that peroxiredoxin 3 (Prx3), a thioredoxin-dependent mitochondrial peroxidase, is highly expressed in 3T3-L1 adipocytes compared to preadipocytes. Interestingly, in obese db/db mice and human subjects, adipose Prx3 levels were significantly decreased, indicating its association with obesity. We therefore employed Prx3 knockout (KO) mice and transfected 3T3-L1 cells to examine the role of endogenous Prx3 in adipocyte metabolism. Prx3 KO mice had increased fat mass compared to wild-type due to adipocyte hypertrophy. Increased adipogenic transcription factors and lipogenic gene expression during differentiation of adipose tissue-derived stem cells from Prx3-deficient mice confirmed that these adipocytes are likely to accumulate fat. Mitochondrial protein carbonylation in Prx3 KO adipose tissue and mitochondrial superoxide level in Prx3 knockdown 3T3-L1 cells were increased showing aberrant regulation of oxidative stress. Proteomic analysis and gene expression analysis of Prx3 KO mice adipocytes also showed defect in mitochondria biogenesis along with enzymes involved in glucose/lipid metabolism and oxidative phosphorylation. In addition, expression level of adiponectin was downregulated and plasminogen activator inhibitor-1 was upregulated in Prx3 KO adipocytes. Impaired glucose tolerance and insulin resistance further implied metabolic dysregulation in Prx3 KO mice. Innovation and Conclusion: These data suggest that endogenous Prx3 may play an essential role in maintaining normal characteristics of adipocytes and that defect in Prx3 alters mitochondrial redox state and function, and adipokine expression in adipocytes leading to metabolic alteration. Antioxid. Redox Signal. 16,[229][230][231][232][233][234][235][236][237][238][239][240][241][242][243]

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Metabolic syndrome and mitochondrial function: Molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function

Cited by 86 publications

References 162 publications

Mitochondrial dysfunction and HIF1α stabilization in inflammation

Mitochondrial dysfunction and HIF1α stabilization in inflammation

Identification of the novel protein FAM172A, and its up-regulation by high glucose in human aortic smooth muscle cells

Peroxiredoxin 3 Is a Key Molecule Regulating Adipocyte Oxidative Stress, Mitochondrial Biogenesis, and Adipokine Expression

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