Altered circulating mitochondrial DNA and increased inflammation in patients with diabetic retinopathy

Malik, Afshan N.; Parsade, Chandani Kiran; Ajaz, Saima; Crosby‐Nwaobi, Roxanne; Gnudi, Luigi; Czajka, Anna; Sivaprasad, Sobha

doi:10.1016/j.diabres.2015.10.006

Cited by 60 publications

(54 citation statements)

References 41 publications

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“…92 These rare mitochondrial genetic diseases commonly result in multiple clinical phenotypes with varying penetrance, likely due to differences in heteroplasmy. 93 In our study, MT-ATP6 variants MT-8706 and MT-8896 (rs202120082), one with MAF > 1% and the other one rare, respectively, were both associated with WHR. MT-ATP6 is part of the proton-transporting portion of ATP synthase, contributing to its rotational mechanism.…”

Section: Mtdna and Metabolic Disease Associationssupporting

confidence: 48%

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Kraja¹,

Liu

Fetterman

et al. 2019

The American Journal of Human Genetics

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109

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Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNAþ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p % 5EÀ04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p % 1EÀ03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p % 1EÀ06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis-and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

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Section: Mtdna and Metabolic Disease Associationssupporting

confidence: 48%

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Kraja¹,

Liu

Fetterman

et al. 2019

The American Journal of Human Genetics

Self Cite

109

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“…The absolutely novel finding of higher mtDNA content in the lymphocytes of patients with CD compared to that of HC strongly suggests a compensatory induction of mitochondrial biogenesis in patients’ cells, triggered by the CD‐associated oxidative stress that might originate low doses of ROS also from mitochondria and stimulate organelles proliferation. This phenomenon has already been demonstrated in ageing human skeletal muscle or, more recently, in patients with diabetic retinopathy . Furthermore, the disease‐related oxidative stress characterizing various pathologies has been shown to affect the mtDNA level of patients’ blood cells suggesting such mtDNA content as a valuable indicator of mitochondrial dysfunction .…”

Section: Discussionmentioning

confidence: 85%

“…P: Mann-Whitney test diabetic retinopathy. 40 Furthermore, the disease-related oxidative stress characterizing various pathologies 41 has been shown to affect the mtDNA level of patients' blood cells suggesting such mtDNA content as a valuable indicator of mitochondrial dysfunction. 42 The mitochondrial compensatory response also includes the patients' increased activity of the mitochondrial MnSOD.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria and redox balance in coeliac disease: A case‐control study

Picca

Riezzo

Lezza

et al. 2018

Eur J Clin Investigation

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“…We previously proposed that blood samples from DR patients could be useful for the detection of systemic mitochondrial dysfunction. In a cross-sectional study comprising of 220 patients, we showed that circulating mtDNA levels were independently associated with DR, showing a biphasic response to the disease, and in parallel, we detected increased inflammation and some evidence of mtDNA damage in DR patients [11].…”

Section: Introductionmentioning

confidence: 61%

The Detection and Partial Localisation of Heteroplasmic Mutations in the Mitochondrial Genome of Patients with Diabetic Retinopathy

Malik

Rosa

Menezes

et al. 2019

IJMS

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Diabetic retinopathy (DR) is a common complication of diabetes and a major cause of acquired blindness in adults. Mitochondria are cellular organelles involved in energy production which contain mitochondrial DNA (mtDNA). We previously showed that levels of circulating mtDNA were dysregulated in DR patients, and there was some evidence of mtDNA damage. In the current project, our aim was to confirm the presence of, and determine the location and prevalence of, mtDNA mutation in DR. DNA isolated from peripheral blood from diabetes patients (n = 59) with and without DR was used to amplify specific mtDNA regions which were digested with surveyor nuclease S1 to determine the presence and location of heteroplasmic mtDNA mutations were present. An initial screen of the entire mtDNA genome of 6 DR patients detected a higher prevalence of mutations in amplicon P, covering nucleotides 14,443 to 1066 and spanning the control region. Further analysis of 42 subjects showed the presence of putative mutations in amplicon P in 36% (14/39) of DR subjects and in 10% (2/20) non-DR subjects. The prevalence of mutations in DR was not related to the severity of the disease. The detection of a high-prevalence of putative mtDNA mutations within a specific region of the mitochondrial genome supports the view that mtDNA damage contributes to DR. The exact location and functional impact of these mutations remains to be determined.

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Altered circulating mitochondrial DNA and increased inflammation in patients with diabetic retinopathy

Cited by 60 publications

References 41 publications

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Mitochondria and redox balance in coeliac disease: A case‐control study

The Detection and Partial Localisation of Heteroplasmic Mutations in the Mitochondrial Genome of Patients with Diabetic Retinopathy

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