Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their
development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic
rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DNmtFHH and T2DNmtWistar, where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar
the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DNmtFHH and T2DNmtWistar showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure,
thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects
of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no
abnormalities, but at 12 months of age the T2DNmtFHH showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II
activity within the electron transport chain was found only in T2DNmtFHH, which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DNmtFHH were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence
that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may
explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction.
"MtDNA encodes seven subunits of respiratory chain, Complex I ND1 to ND6 and ND4L, cyt b (subunit of Complex III), three subunits of Complex IV, that is, cytochrome c oxidase, subunits 1, 2, 3, and ATP synthase subunits 6 and 8, plus 22 tRNAs and two ribosomal RNAs. Certain mtDNA mutations in these mt genes should lead to oxidative stress and initiate β cell dysfunction , such as in the heart . Thus an ATP8 subunit mutation has been associated with increased mitochondrial superoxide generation, impaired GSIS, and increased β cell mass adaptation . "
[Show abstract][Hide abstract] ABSTRACT: We reviewed mechanisms that determine reactive oxygen species (redox) homeostasis, redox information signaling and metabolic/regulatory function of autocrine insulin signaling in pancreatic β cells, and consequences of oxidative stress and dysregulation of redox/information signaling for their dysfunction. We emphasize the role of mitochondrion in β cell molecular physiology and pathology, including the antioxidant role of mitochondrial uncoupling protein UCP2. Since in pancreatic β cells pyruvate cannot be easily diverted towards lactate dehydrogenase for lactate formation, the respiration and oxidative phosphorylation intensity are governed by the availability of glucose, leading to a certain ATP/ADP ratio, whereas in other cell types, cell demand dictates respiration/metabolism rates. Moreover, we examine the possibility that type 2 diabetes mellitus might be considered as an inevitable result of progressive self-accelerating oxidative stress and concomitantly dysregulated information signaling in peripheral tissues as well as in pancreatic β cells. It is because the redox signaling is inherent to the insulin receptor signaling mechanism and its impairment leads to the oxidative and nitrosative stress. Also emerging concepts, admiting participation of redox signaling even in glucose sensing and insulin release in pancreatic β cells, fit in this view. For example, NADPH has been firmly established to be a modulator of glucose-stimulated insulin release.
Oxidative Medicine and Cellular Longevity 12/2012; 2012(6):932838. DOI:10.1155/2012/932838 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetically modified mouse models have unparalleled power to determine the mechanisms behind different processes involved in the molecular and physiologic etiology of various classes of human pulmonary hypertension (PH). Processes known to be involved in PH for which there are extensive mouse models available include the following: (1) Regulation of vascular tone through secreted vasoactive factors; (2) regulation of vascular tone through potassium and calcium channels; (3) regulation of vascular remodeling through alteration in metabolic processes, either through alteration in substrate usage or through circulating factors; (4) spontaneous vascular remodeling either before or after development of elevated pulmonary pressures; and (5) models in which changes in tone and remodeling are primarily driven by inflammation. PH development in mice is of necessity faster and with different physiologic ramifications than found in human disease, and so mice make poor models of natural history of PH. However, transgenic mouse models are a perfect tool for studying the processes involved in pulmonary vascular function and disease, and can effectively be used to test interventions designed against particular molecular pathways and processes involved in disease.
[Show abstract][Hide abstract] ABSTRACT: MiRNAs are post-transcriptional regulators of protein expression and they bind to complementary sequences in the 3’UTRs of their target mRNA either performing transcript degradation or translational inhibition. It is accepted that they play a role in the defect of β-cells to secrete enough insulin so trigger type 2 diabetes mellitus (T2DM). T2DM is a common, complex, metabolic disorder. It can characterize with these defects; insulin resistance in peripheral tissues and beta‐cell dysfunction or reduced beta cell mass. Due to these defects blood glucose level increase. At the same time there is a real that T2DM is not because of only these reasons. Also genetic actions seems to be involved in the development of T2DM. This project focuses on a microRNA that has been shown to be involved in glucose‐induced beta‐cell dysfunction. The key findings from other studies were that miR‐29a is up‐regulated by glucose in beta‐cells and decrease glucose‐stimulated insulin secretion by inducing decreased activity of the electron transport chain. Recently two publications have shown that microRNAs are present in the mitochondria, suggesting that microRNAs can regulate mitochondrial gene-expression. So in this project the target sequence was searched for miR29-a. Based on this information it was tried to identify any targets of miR-29a in the mitochondrial encoded subunits of the electron transport chain. In this project we identified potential targets of miR-29a in: in ND6, ND5 and D-LOOP. The oligos were designed as having a predicted target sequence for miR29-a and transferred to a vector which has luc2 gene. These vectors were copied in E.coli cells then transfected HEK cells for luciferase assay. Unfortunetly the luciferase assay’s data and t-test showed that there is no target sequence in ND6. During the experiments because of the unknown reasons we could not use other oligos ND5 and D-LOOP. But for say a certain answer this experiment must repeat
Yftach Gepner, Rachel Golan, Ilana Harman-Boehm, Yaakov Henkin, Dan Schwarzfuchs, Ilan Shelef, Ronen Durst, Julia Kovsan, Arkady Bolotin, Eran Leitersdorf, [...], Benjamin Sarusi, Sivan Ben-Avraham, Anders Helander, Uta Ceglarek, Michael Stumvoll, Matthias Blüher, Joachim Thiery, Assaf Rudich, Meir J Stampfer, Iris Shai
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