Epigenetic Modification of Mitochondrial DNA in the Development of Diabetic Retinopathy

Mishra, Manish; Kowluru, Renu A.

doi:10.1167/iovs.15-16937

Cited by 123 publications

(150 citation statements)

References 49 publications

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“…In addition to the nuclear DNA, mtDNA is also susceptible to epigenetic modifications as this small DNA has ~450 CpG sites and ~4500 cytosine residues at non-CpG sites. Increased mtDNA methylation is observed in chronic diseases, including cancer [80], and our recent studies have shown that in diabetes, increased Dnmt1 expression in the retinal mitochondria hypermethylates its mtDNA [81]. Due to hypermethylation of the D-loop region, mtDNA transcription is impaired and…”

Section: Epigenetic Modifications Oxidative Stress and Diabetic Retimentioning

confidence: 99%

Oxidative stress, mitochondrial damage and diabetic retinopathy

Kowluru

Mishra

2015

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

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264

236

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Diabetes has emerged as an epidemic of the 21st century, and retinopathy remains the leading cause of blindness in young adults and the mechanism of this blinding disease remains evasive. Diabetes-induced metabolic abnormalities have been identified, but a causal relationship between any specific abnormality and the development of this multi-factorial disease is unclear. Reactive oxygen species (ROS) are increased and the antioxidant defense system is compromised. Increased ROS result in retinal metabolic abnormalities, and these metabolic abnormalities can also produce ROS. Sustained exposure to ROS damages the mitochondria and compromises the electron transport system (ETC), and, ultimately, the mitochondrial DNA (mtDNA) is damaged. Damaged mtDNA impairs its transcription, and the vicious cycle of ROS continues to propagate. Many genes important in generation and neutralization of ROS are also epigenetically modified further increasing ROS, and the futile cycle continues to fuel in. Antioxidants have generated beneficial effects in ameliorating retinopathy in diabetic rodents, but limited clinical studies have not been encouraging. With the ongoing use of antioxidants for other chronic diseases, there is a need for a controlled trial to recognize their potential in ameliorating the development of this devastating disease.

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Section: Epigenetic Modifications Oxidative Stress and Diabetic Retimentioning

confidence: 99%

Oxidative stress, mitochondrial damage and diabetic retinopathy

Kowluru

Mishra

2015

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

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264

236

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“…Zheng et al reported that aberrant mtDNA Dloop methylation is associated with insulin resistance in obese individuals [93]. Interestingly, the retinal microvasculature of diabetic retinopathy patients shows increase in D-loop methylation [94].…”

Section: Current Studies On Mitochondrial Epigenetics In Human Diseasesmentioning

confidence: 99%

Mitochondrial Epigenetics and Environmental Exposure

Lambertini

Byun

2016

Curr Envir Health Rpt

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The rising toll of chronic and debilitating diseases brought about by the exposure to an ever expanding number of environmental pollutants and socio-economic factors is calling for action. The understanding of the molecular mechanisms behind the effects of environmental exposures can lead to the development of biomarkers that can support the public health fields of both early diagnosis and intervention to limit the burden of environmental diseases. The study of mitochondrial epigenetics carries high hopes to provide important biomarkers of exposure and disease. Mitochondria are in fact on the frontline of the cellular response to the environment. Modifications of the epigenetic factors regulating the mitochondrial activity are emerging as informative tools that can effectively report on the effects of the environment on the phenotype. Here, we will discuss the emerging field of mitochondrial epigenetics. This review describes the main epigenetic phenomena that modify the activity of the mitochondrial DNA including DNA methylation, long and short non-coding RNAs. We will discuss the unique pattern of mitochondrial DNA methylation, describe the challenges of correctly measuring it, and report on the existing studies that have analysed the correlation between environmental exposures and mitochondrial DNA methylation. Finally, we provide a brief account of the therapeutic approaches targeting mitochondria currently under consideration.

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“…In fact, Mishra and Kowluru have recently discovered that modulation of Dnmt1 by pharmaceutical or molecular means could help maintain mitochondrial integrity and serve as a potential strategy to inhibit/ halt the development of DR [113].…”

Section: The Role Of Epigenetics In the Pathogenesis Of Diabetic Retimentioning

confidence: 99%

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

Cilenšek¹,

Ramuš²,

Petrovič³

et al. 2016

Role of Biomarkers in Medicine

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Changes in dietary habits and lifestyles associated with rapid economic growth have dramatically increased the incidence of diabetes and related vascular complications. Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with both environmental and genetic factors. Several metabolic abnormalities are implicated in its pathogenesis; however, the exact mechanism remains to be determined. Among them, oxidative stress is expected to play an important role.Environmental, genetic, and epigenetic factors affecting the oxidative stress responsible for DR are reviewed in this paper. The knowledge about genetic biomarkers of DR is quite extensive, whereas the awareness about epigenetics and epigenetic markers is only beginning to be understood.Modulation of epigenetic changes by pharmaceutical means may provide a potential strategy to retard the progression of DR. In addition to the intense medical management, these strategies include dietary measures (antioxidants) and the introduction of epigenetic drugs, such as inhibitors of DNA methylation and histone demethylases.

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Epigenetic Modification of Mitochondrial DNA in the Development of Diabetic Retinopathy

Abstract: Hypermethylation of mtDNA in diabetes impairs its transcription, resulting in dysfunctional mitochondria and accelerated capillary cell apoptosis. Regulation of mtDNA methylation has potential to restore mitochondrial homeostasis and inhibit/retard the development of diabetic retinopathy.

Cited by 123 publications

References 49 publications

Oxidative stress, mitochondrial damage and diabetic retinopathy

Oxidative stress, mitochondrial damage and diabetic retinopathy

Mitochondrial Epigenetics and Environmental Exposure

Oxidative Stress Biomarkers for Diabetic Retinopathy and Medical Management Affecting Oxidative Stress

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