As many diseases have been shown to have several or indirect causes (i.e. are multifactorial) the question is what is the relative importance of each factor in a given disease? Also, what happens when some diseases, although apparently disparate, share causative factors and/or tissue pathologies? Host inflammation response mechanisms are largely shared by the body’s different tissues and systems and only recently has special attention been paid to the possible linkages among chronic periodontitis and other chronic systemic diseases. The aim of this review was to consider and discuss the mounting evidence that the basis for the inter-relationships between chronic periodontitis and atheromatous disease and diabetes lie at a fundamental intracellular level, namely oxidative stress and mitochondrial dysfunction, as a meeting background among such chronic diseases and periodontitis.

Obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction?

Mitochondrial dysfunction and complications associated with diabetes

Enabling Technologies for Personalized and Precision Medicine

Retinal mitochondria become dysfunctional in diabetes and the production of superoxide radicals is increased; over-expression of MnSOD abrogates mitochondrial dysfunction and prevents the development of diabetic retinopathy. The mitochondrial DNA (mtDNA) is particularly prone to oxidative damage. The aim of this study is to examine the role of MnSOD in the maintenance of mtDNA. The effect of MnSOD mimic, MnTBAP or over-expression of MnSOD on glucose-induced alterations in mtDNA homeostasis and its functional consequence was determined in retinal endothelial cells. Exposure of retinal endothelial cells to high glucose increased mtDNA damage and compromised the DNA repair machinery. The gene expressions of mitochondrial-encoded proteins of the electron transport chain complexes were decreased. Inhibition of superoxide radicals by either MnTBAP or by over-expression of MnSOD prevented mtDNA damage and protected mitochondrial-encoded genes. Thus, the protection of mtDNA from glucose-induced oxidative damage is one of the plausible mechanisms by which MnSOD ameliorates the development of diabetic retinopathy.

Oxidative damage of mitochondrial DNA in diabetes and its protection by manganese superoxide dismutase.

Objectives To analyze the frequency of mitochondrial DNA (mtDNA) damage in patients with primary open-angle glaucoma. Oxidative damage plays a major role in glaucoma pathogenesis. Since no environmental risk factor for glaucoma is recognized, we focused our attention on mitochondria, the main endogenous source of reactive oxygen species. Methods Mitochondrial damage was evaluated analyzing a common mtDNA deletion by real-time polymerase chain reaction in trabecular meshwork collected at surgery from 79 patients with primary open-angle glaucoma and 156 unaffected matched controls. In the same samples, polymorphisms of genes encoding for antioxidant defenses ( GSTM1 ), repair of oxidative DNA damage ( OGG1 ), and apoptosis ( FAS ) were tested. Results Mitochondrial DNA deletion was dramatically increased (5.32-fold; P  = .01) in trabecular meshwork of patients with glaucoma vs controls. This finding was paralleled by a decrease in the number of mitochondria per cell (4.83-fold; P P GSTM1- null genotype showed increased amounts of mtDNA deletion and a decreased number of mitochondria per cell as compared with GSTM1- positive subjects. Patients bearing a FAS homozygous mutation showed only a decreased number of mitochondria per cell. Conclusions Obtained results indicate that mitochondrion is targeted by the glaucomatous pathogenic processes. Some subjects bearing adverse genetic assets are more susceptible to this event. Clinical Relevance Oxidative damage to the trabecular meshwork exerts a pathogenic role in glaucoma inducing mitochondrial damage and triggering apoptosis and cell loss. This issue may be useful to develop new glaucoma molecular biomarkers and to identify high-risk subjects.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/425838/els05001_724_730.pdf

Mitochondrial damage in the trabecular meshwork of patients with glaucoma.

There is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy. This study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease. Haplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046). Our data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.

/pdf/mitochondrial-dna-haplogroup-t-is-associated-with-coronary-35bmm4us1e.pdf

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

Background
The pivotal role of mitochondria in energy production and free radical generation suggests that the mitochondrial genome could have an important influence on the expression of multifactorial age related diseases. Substitution of T to C at nucleotide position 16189 in the hypervariable D-loop of the control region (CR) of mitochondrial DNA (mtDNA) has attracted research interest because of its suspected association with various multifactorial diseases. The aim of the present study was to compare the frequency of this polymorphism in the CR of mtDNA in patients with coronary artery disease (CAD, n = 482) and type 2 diabetes mellitus (T2DM, n = 505) from two study centers, with healthy individuals (n = 1481) of Middle European descent in Austria.

/pdf/the-mitochondrial-t16189c-polymorphism-is-associated-with-3e1nfelg98.pdf

Danijela Santic

Papers

Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study

The Mitochondrial T16189C Polymorphism Is Associated with Coronary Artery Disease in Middle European Populations