Increased peripheral blood mitochondrial DNA in type 2 diabetic patients with nephropathy

Malik, Afshan N.; Shahni, Rojeen; Iqbal, Masud

doi:10.1016/j.diabres.2009.07.002

Cited by 55 publications

(49 citation statements)

References 15 publications

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“…Thus, by influencing the concentration of adenosine that is present within mitochondria, ENT3 can regulate mitochondrial function and modifications in the intramitochondrial nucleoside pool through inactivating mutations may culminate in deleterious consequences on mitochondria function. It is therefore possible that depletion of ENT3 in β-cell mitochondria causes excessive build up of nucleosides that are required for the synthesis of mtDNA, which in turn causes oxidative stress and inflammation associated with increased mtDNA content, leading to mtDNA damage/mutation and mitochondrial dysfunction [22,23,[43][44][45]. This theory is supported by our experimental observations of a 1.7-fold increase in mitochondrial copy number following siRNAs-mediated knockdown of β-cell ENT3 expression.…”

Section: Discussionsupporting

confidence: 56%

“…Mitochondria contain their own DNA genome and changes in mtDNA content have been proposed as a biomarker of mitochondrial dysfunction [17,22,23]. Mitochondrial nucleoside transport via ENTs may be important in mitochondrial DNA synthesis and repair so experiments were performed to investigate if ENT3 depletion affected mtDNA content.…”

Section: Depletion Of Ent3 Increases β-Cell Mtdna Content and Impairsmentioning

confidence: 99%

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Equilibrative nucleoside transporter 3 depletion in β-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes

Liu¹,

Czajka²,

Malik³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Loss of function recessive mutations in the SLC29A3 gene that encodes human equilibrative nucleoside transporter 3 (ENT3) have been identified in patients with pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID). ENT3 is a member of the equilibrative nucleoside transporter (ENT) family whose primary function is mediating transport of nucleosides and nucleobases. The aims of this study were to characterise ENT3 expression in islet β-cells and identify the effects of its depletion on β-cell mitochondrial activity and apoptosis. RT-PCR amplification identified ENT3 expression in human and mouse islets and exocrine pancreas, and in MIN6 β-cells. Immunohistochemistry using human and mouse pancreas sections exhibited extensive ENT3 immunostaining of β-cells, which was confirmed by co-staining with an anti-insulin antibody. In addition, exposure of dispersed human islet cells and MIN6 β-cells to MitoTracker and an ENT3 antibody showed co-localisation of ENT3 to β-cell mitochondria. Consistent with this, Western blot analysis confirmed enhanced ENT3 immunoreactivity in β-cell mitochondria-enriched fractions. Furthermore, ENT3 depletion in β-cells increased mitochondrial DNA content and promoted an energy crisis characterised by enhanced ATP-linked respiration and proton leak. Finally, inhibition of ENT3 activity by dypridamole and depletion of ENT3 by siRNA-induced knockdown resulted in increased caspase 3/7 activities in β-cells. These observations demonstrate that ENT3 is predominantly expressed by islet β-cells where it co-localises with mitochondria. Depletion of ENT3 causes mitochondrial dysfunction which is associated with enhanced β-cell apoptosis. Thus, apoptotic loss of islet β-cells may contribute to the occurrence of autoantibody-negative insulin-dependent diabetes in individuals with non-functional ENT3 mutations.

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Section: Discussionsupporting

confidence: 56%

Section: Depletion Of Ent3 Increases β-Cell Mtdna Content and Impairsmentioning

confidence: 99%

Equilibrative nucleoside transporter 3 depletion in β-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes

Liu¹,

Czajka²,

Malik³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

show abstract

“…At this point, it is relevant to mention that both total number of mitochondria and copy number of mtDNA change during oxidative stress (Liu et al, 2003). Malik et al (2009) reported that mtDNA copy numbers show a significant increase in peripheral blood of patients with diabetic nephropathy, which was associated also with the presence of oxidative stress markers. Song et al (2007) reported that mtDNA content is linked to the sensitivity to insulin in offspring from type 2 diabetic patients.…”

Section: Perspectivementioning

confidence: 98%

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

Alvarado-Vásquez¹

2015

Experimental Gerontology

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“…The most commonly used method used measure MtDNA content in a cell is to quantify the mitochondrial genome versus nuclear genome ratio, termed Mt/N (7,(14)(15)(16) MtDNA from human samples (16). However, a similar approach has not been described for mouse MtDNA and there is little information in the literature about whether mouse MtDNA is present as NumtS in the nuclear genome.…”

Section: Introductionmentioning

confidence: 99%

Accurate quantification of mouse mitochondrial DNA without co-amplification of nuclear mitochondrial insertion sequences

2016

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(2016). Accurate quantification of mouse mitochondrial DNA without co-amplification of nuclear mitochondrial insertion sequences. MITOCHONDRION. DOI: 10.1016DOI: 10. /j.mito.2016 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbbreviationsMtDNA-mitochondrial DNA NumtS-nuclear mitochondrial insertion sequence A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 Abstract:Background: Mitochondria contain extra-nuclear genome in the form of mitochondrial DNA (MtDNA), damage to which can lead to inflammation and bioenergetic deficit. Changes inMtDNA levels are increasingly used as a biomarker of mitochondrial dysfunction. We previously reported that in humans, fragments in the nuclear genome known as nuclear mitochondrial insertion sequences (NumtS) affect accurate quantification of MtDNA. In the current paper our aim was to determine whether mouse NumtS affect the quantification ofMtDNA and to establish a method designed to avoid this. Methods:The existence of NumtS in the mouse genome was confirmed using blast N, unique MtDNA regions were identified using FASTA, and MtDNA primers which do not co-amplify NUMTs were designed and tested. MtDNA copy numbers were determined in a range of mouse tissues as the ratio of the mitochondrial and nuclea...

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Increased peripheral blood mitochondrial DNA in type 2 diabetic patients with nephropathy

Cited by 55 publications

References 15 publications

Equilibrative nucleoside transporter 3 depletion in β-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes

Equilibrative nucleoside transporter 3 depletion in β-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes

Circulating cell-free mitochondrial DNA as the probable inducer of early endothelial dysfunction in the prediabetic patient

Accurate quantification of mouse mitochondrial DNA without co-amplification of nuclear mitochondrial insertion sequences

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