Role of mitochondrial DNA variation in the pathogenesis of diabetes mellitus

Kwak, Soo Heon; Park, Kyong Soo

doi:10.2741/4447

Cited by 23 publications

(11 citation statements)

References 105 publications

(118 reference statements)

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“…Increased mitochondrial fission may impair endothelial function via increased ROS in DM (Shenouda et al, 2011). Decreased OXPHOS and fatty acid oxidation in insulin-sensitive tissues has been reported (Kwak and Park, 2016). Mitochondrial uncoupling may protect the mitochondrial matrix against lipid-induced mitochondrial damage (Schrauwen and Hesselink, 2004).…”

Section: Mitochondrial Haplogroups Associated With Disease In East Asiamentioning

confidence: 92%

Contribution of Mitochondrial DNA Variation to Chronic Disease in East Asian Populations

Sun

Wei

Zheng

et al. 2019

Front. Mol. Biosci.

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Mitochondria are the main producers of energy in eukaryotic cells. Mitochondrial dysfunction is associated with specific mitochondrial DNA (mtDNA) variations (haplogroups), and these variations can contribute to human disease. East Asian populations show enrichment of many mitochondrial haplogroups, including A, B, D, G, M7, M8, M9, N9, R9, and exhibit half of the known haplogroups of worldwide. In this review, we summarize the current research in the field of mtDNA variation and associated disease in East Asian populations and discuss the physiological and pathological relevance of mitochondrial biology. mtDNA haplogroups are associated with various metabolic disorders ascribed to altered oxidative phosphorylation. The same mitochondrial haplogroup can show either a negative or positive association with different diseases. Mitochondrial dynamics, mitophagy, and mitochondrial oxidative stress, ultimately influence susceptibility to various diseases. In addition, mitochondrial retrograde signaling pathways may have profound effects on nuclear-mitochondrial interactions, affecting cellular morphology, and function. Other complex networks including proteostasis, mitochondrial unfolded protein response and reactive oxygen species signaling may also play pivotal roles in metabolic performance.

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Section: Mitochondrial Haplogroups Associated With Disease In East Asiamentioning

confidence: 92%

Contribution of Mitochondrial DNA Variation to Chronic Disease in East Asian Populations

Sun

Wei

Zheng

et al. 2019

Front. Mol. Biosci.

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“…Genetics also influences susceptibility to mitochondrial and metabolic dysfunction. For example, the mtDNA genetic variant at 16 189 from T to C has been associated with increased oxidative damage, altered antioxidant status and onset of type two diabetes [59][60][61]. Furthermore, different mtDNA haplogroups have been increasingly associated with individual susceptibility to toxic side effects observed in some patients [62][63][64][65][66].…”

Section: Toxic Effects Of Pharmacological Agents On Mitochondrial Funmentioning

confidence: 99%

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

Stoker

Newport

Hulit³

et al. 2019

Biochemical Society Transactions

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Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

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“…It is well known that the mtDNA 3243 A>G variation results in maternally inherited diabetes and deafness. The frequency of this mutation is estimated to be approximately 0.5% to 3% in East Asian diabetes patients [ 16 ]. However, the frequency is even lower in Europeans.…”

Section: Etiologic Risk Factorsmentioning

confidence: 99%

Pathophysiology of Type 2 Diabetes in Koreans

Kwak

Park

2018

Endocrinol Metab

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The pathophysiology of type 2 diabetes is characterized by variable degrees of insulin resistance and impaired insulin secretion. Both genetic and environmental factors serve as etiologic factors. Recent genetic studies have identified at least 83 variants associated with diabetes. A significant number of these loci are thought to be involved in insulin secretion, either through β-cell development or β-cell dysfunction. Environmental factors have changed rapidly during the past half century, and the increased prevalence of obesity and diabetes can be attributed to these changes. Environmental factors may affect epigenetic changes and alter susceptibility to diabetes. A recent epidemiologic study revealed that Korean patients with type 2 diabetes already had impaired insulin secretion and insulin resistance 10 years before the onset of diabetes. Those who developed diabetes showed impaired β-cell compensation with an abrupt decrease in insulin secretion during the last 2 years before diabetes developed. The retrograde trajectory of the disposition index differed according to the baseline subgroups of insulin secretion and insulin sensitivity. We hope that obtaining a more detailed understanding of the perturbations in the major pathophysiologic process of diabetes on the individual level will eventually lead to the implementation of precision medicine and improved patient outcomes.

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Role of mitochondrial DNA variation in the pathogenesis of diabetes mellitus

Cited by 23 publications

References 105 publications

Contribution of Mitochondrial DNA Variation to Chronic Disease in East Asian Populations

Contribution of Mitochondrial DNA Variation to Chronic Disease in East Asian Populations

Impact of pharmacological agents on mitochondrial function: a growing opportunity?

Pathophysiology of Type 2 Diabetes in Koreans

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