mitoquinone and Diabetes-Mellitus--Type-2

Mitochondria control various processes in cellular metabolic homeostasis, such as adenosine triphosphate production, generation and clearance of reactive oxygen species, control of intracellular Ca

Topics: Diabetes Mellitus, Type 2; Homeostasis; Humans; Metabolic Syndrome; Mitochondria; Organophosphorus Compounds; Ubiquinone

Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and hypertension. Although the pathogenesis of diabetic cardiomyopathy has yet to be fully elucidated, aberrations in cardiac substrate metabolism and energetics are thought to be key drivers. These aberrations include excessive fatty acid utilisation and storage, suppressed glucose oxidation and impaired mitochondrial oxidative phosphorylation. An appreciation of how these abnormalities arise and synergise to promote adverse cardiac remodelling is critical to their effective amelioration. This review focuses on disturbances in myocardial fuel (fatty acids and glucose) flux and energetics in type 2 diabetes, how these disturbances relate to the development of diabetic cardiomyopathy and the potential therapeutic agents that could be used to correct them.

Topics: Antioxidants; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Energy Metabolism; Fatty Acids; Glucose; Humans; Mitochondria, Heart; Myocardium; Organophosphorus Compounds; Oxidative Phosphorylation; Oxidative Stress; Perhexiline; Ranolazine; Trimetazidine; Ubiquinone

Type 2 diabetic hearts are more vulnerable to myocardial ischemia reperfusion (MIR) injury, which involves decreased mitophagy status with unknown mechanisms. MitoQ, a mitochondria-targeted antioxidant, has been shown to have protection against ischemia reperfusion injury through upregulating mitophagy. The aim of this study was to investigate the effects of MitoQ on myocardium during MIR injury in type 2 diabetes (T2D). Herein, this study discovered that type 2 diabetic hearts with PINK1/Parkin downregulation suffered more MIR injury accompanied by reduced mitophagy. Treatment with MitoQ significantly decreased the levels of CK-MB, LDH, myocardial infarction, myocardial pathological damage, and cardiomyocytes apoptosis, while it improved cardiac function, mitophagy status, and PINK1/Parkin pathway in vivo study. Furthermore, MitoQ significantly reduced high glucose/high fat and hypoxia/reoxygenation induced injury in H9C2 cells as evidenced by reduced cardiomyocytes apoptosis and ROS production, and increased cell viability, the level of mitochondrial membrane potential, PINK1/Parkin expression. However, mitochondrial division inhibitor (mdivi-1), an inhibitor of mitophagy, reversed the improvement and protein expression levels of PINK1/Parkin pathway in vitro models. In conclusion, MIR induced more severe damage in T2D by reduction of mitophagy. MitoQ can confer cardioprotection following MIR in T2D by mitophagy up-regulation via PINK1/Parkin pathway.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Mitochondria; Mitophagy; Myocardial Reperfusion Injury; Organophosphorus Compounds; Protein Kinases; Rats; Rats, Sprague-Dawley; Ubiquinone; Ubiquitin-Protein Ligases

Previous work by ourselves and others showed that mitoquinone (mitoQ) reduced oxidative damage and prevented hepatic fat accumulation in mice made obese with high-fat (HF) feeding. Here we extended these studies to examine the effect of mitoQ on parameters affecting liver function in rats treated with HF to induce obesity and in rats treated with HF plus streptozotocin (STZ) to model a severe form of type 2 diabetes. In prior reported work, we found that mitoQ significantly improved glycemia based on glucose tolerance data in HF rats but not in the diabetic rats. Here we found only non-significant reductions in insulin and glucose measured in the fed state at sacrifice in the HF mice treated with mitoQ. Metabolomic data showed that mitoQ altered several hepatic metabolic pathways in HF-fed obese rats toward those observed in control normal chow-fed non-obese rats. However, mitoQ had little effect on pathways observed in the diabetic rats, wherein diabetes itself induced marked pathway aberrations. MitoQ did not alter respiration or membrane potential in isolated liver mitochondria. MitoQ reduced liver fat and liver hydroperoxide levels but did not improve liver function as marked by circulating levels of aspartate and alanine aminotransferase (ALT). In summary, our results for HF-fed rats are consistent with past findings in HF-fed mice indicating decreased liver lipid hydroperoxides (LPO) and improved glycemia. However, in contrast to the HF obese mice, mitoQ did not improve glycemia or reset perturbed metabolic pathways in the diabetic rats.

Topics: Animals; Blood Glucose; Cell Respiration; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Fatty Liver; Insulin; Lipid Metabolism; Liver; Male; Membrane Potential, Mitochondrial; Metabolomics; Mitochondria, Liver; Obesity; Organophosphorus Compounds; Oxidative Stress; Rats, Sprague-Dawley; Ubiquinone

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Hypoglycemic Agents; Male; Mitochondria; Obesity; Organophosphorus Compounds; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Streptozocin; Ubiquinone

Can we use a mitochondrial-targeted antioxidant (Mitoquinone) during in vitro embryo culture to rescue developmental competence of oocytes matured under lipotoxic conditions, exhibiting mitochondrial dysfunction and oxidative stress?. Supplementation of embryo culture media with Mitoquinone reduced oxidative stress and prevented mitochondrial uncoupling in embryos derived from metabolically compromised oocytes in vitro, leading to higher blastocyst rates and lower blastomeric apoptosis.. Maternal metabolic disorders, such as obesity and type-II diabetes are associated with hyperlipidemia and elevated free fatty acid (FFA) concentrations in the ovarian follicular fluid (FF). Oocyte maturation under these lipotoxic conditions results in increased oxidative stress levels, mitochondrial dysfunction, reduced developmental competence and disappointing IVF results.. A well-described bovine oocyte IVM model was used, where a pathophysiologically relevant elevated FF concentrations of palmitic acid (PA; 150 μM or 300 μM) were added to induce oxidative stress. After fertilization (Day 0, D0), zygotes were in vitro cultured (IVC, from D1 to D8) in standard fatty acid-free media in the presence or absence of Mitoquinone or its carrier triphenyl-phosphonium.. Embryo cleavage and fragmentation (D2) and blastocyst rates (D8) were recorded. Mitochondrial activity and oxidative stress in cleaved embryos at D2 were determined using specific fluorogenic probes and confocal microscopy. D8 blastocysts were used to (i) examine the expression of marker genes related to mitochondrial unfolded protein responses (UPRmt; HSPD1 and HSPE1), mitochondrial biogenesis (TFAM), endoplasmic reticulum (ER) UPR (ATF4, ATF6 and BiP) and oxidative stress (CAT, GPX1 and SOD2) using real time RT-PCR; (ii) determine cell differentiation and apoptosis using CDX-2 and cleaved caspase-3 immunostaining; and (iii) measure mtDNA copy numbers. This was tested in a series of experiments with at least three independent replicates for each, using a total of 2525 oocytes. Differences were considered significant if a P value was <0.05 after Bonferroni correction.. Exposure to PA during IVM followed by culture under control conditions resulted in a significant increase in oxidative stress in embryos at D2. This was associated with a significant reduction in mitochondrial inner membrane potential (uncoupling) compared with solvent control (P < 0.05). The magnitude of these effects was PA-concentration dependent. Consequently, development to the blastocysts stage was significantly hampered. Surviving blastocysts exhibited high apoptotic cell indices and upregulated mRNA expression indicating persistent oxidative stress, mitochondrial and ER UPRs. In contrast, supplementation of PA-derived zygotes with Mitoquinone during IVC (i) prevented mitochondrial uncoupling and alleviated oxidative stress at D2; and (ii) rescued blastocyst quality; normalized oxidative stress and UPR related genes and apoptotic cell indices (P > 0.01 compared with solvent control). Mitoquinone also improved blastocyst rate in PA-exposed groups, an effect that was dependent on PA concentration.. N/A.. This is a fundamental study performed using a bovine in vitro model using PA-induced lipotoxicity during oocyte maturation. PA is the most predominant FFA in the FF that is known to induce lipotoxicity; however, in vivo maturation in patients suffering from maternal metabolic disorders involve more factors that cannot be represented in one model. Nevertheless, focusing on the carryover oxidative stress as a known key factor affecting developmental competence, and considering the novel beneficial rescuing effects of Mitoquinone shown here, we believe this model is of high biological relevance.. Human oocytes collected for IVF treatments from patients with maternal metabolic disorders are vulnerable to lipotoxicity and oxidative stress during in vivo maturation. The results shown here suggest that mitochondrial targeted therapy, such as using Mitoquinone, during IVC may rescue the developmental competence and quality of these compromised oocytes. After further clinical trials, this may be a valuable approach to increase IVF success rates for infertile patients experiencing metabolic disorders.. This study was financially supported by a BOF/KP grant number 34399, from the University of Antwerp, Belgium. W.F.A.M. was supported by a postdoctoral fellowship from the Research Foundation-Flanders (FWO), grant number 12I1417N, Antwerp, Belgium. The Leica SP 8 confocal microscope used in this study was funded by the Hercules Foundation of the Flemish Government (Hercules grant AUHA.15.12). All authors have no financial or non-financial competing interests to declare.

Topics: Animals; Antioxidants; Cattle; Culture Media; Diabetes Mellitus, Type 2; Disease Models, Animal; Embryo, Mammalian; Embryonic Development; Female; Follicular Fluid; Humans; In Vitro Oocyte Maturation Techniques; Infertility, Female; Mitochondria; Obesity; Oocytes; Organophosphorus Compounds; Oxidative Stress; Palmitic Acid; Ubiquinone

It is not known if the mitochondria-targeted antioxidants such as mitoquinone (MitoQ) can modulate oxidative stress and leukocyte-endothelium interactions in T2D patients. We aimed to evaluate the beneficial effect of MitoQ on oxidative stress parameters and leukocyte-endothelium interactions in leukocytes of T2D patients. The study population consisted of 98 T2D patients and 71 control subjects. We assessed metabolic and anthropometric parameters, mitochondrial reactive oxygen species (ROS) production, glutathione peroxidase 1 (GPX-1), NFκB-p65, TNFα and leukocyte-endothelium interactions. Diabetic patients exhibited higher weight, BMI, waist circumference, SBP, DBP, glucose, insulin, HOMA-IR, HbA1c, triglycerides, hs-CRP and lower HDL-c with respect to controls. Mitochondrial ROS production was enhanced in T2D patients and decreased by MitoQ. The antioxidant also increased GPX-1 levels and PMN rolling velocity and decreased PMN rolling flux and PMN adhesion in T2D patients. NFκB-p65 and TNFα were augmented in T2D and were both reduced by MitoQ treatment. Our findings support that the antioxidant MitoQ has an anti-inflammatory and antioxidant action in the leukocytes of T2D patients by decreasing ROS production, leukocyte-endothelium interactions and TNFα through the action of NFκB. These data suggest that mitochondria-targeted antioxidants such as MitoQ should be investigated as a novel means of preventing cardiovascular events in T2D patients.

Topics: Aged; Anthropometry; Anti-Inflammatory Agents; Antioxidants; Diabetes Mellitus, Type 2; Female; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Humans; Leukocytes; Male; Middle Aged; Organophosphorus Compounds; Oxidative Stress; Reactive Oxygen Species; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Ubiquinone

This study evaluated the association between free fatty acid (FFA), ROS generation, mitochondrial dysfunction and bone mineral density (BMD) in type 2 diabetic patients and investigated the molecular mechanism. db/db and high fat (HF)-fed mice were treated by Etomoxir, an inhibitor of CPT1, MitoQ, and PFT-α, an inhibitor of P53. Bone metabolic factors were assessed and BMSCs were isolated and induced to osteogenic differentiation. FFA, lipid peroxidation and mtDNA copy number were correlated with BMD in T2DM patients. Etomoxir, MitoQ and PFT-α significantly inhibited the decrease of BMD and bone breaking strength in db/db and HF-fed mice and suppressed the reduction of BMSCs-differentiated osteoblasts. Etomoxir and MitoQ, but not PFT-α, inhibited the increase of mitochondrial ROS generation in db/db and HF-fed mice and osteoblasts. In addition, Etomoxir, MitoQ and PFT-α significantly inhibited mitochondrial dysfunction in osteoblasts. Moreover, mitochondrial apoptosis was activated in osteoblasts derived from db/db and HF-fed mice, which was inhibited by Etomoxir, MitoQ and PFT-α. Furthermore, mitochondrial accumulation of P53 recruited Bax and initiated molecular events of apoptotic events. These results demonstrated that fatty acid oxidation resulted in ROS generation, activating P53/Bax-mediated mitochondrial apoptosis, leading to reduction of osteogenic differentiation and bone loss in T2DM.

Topics: Adult; Animals; Apoptosis; Benzothiazoles; Bone Density; Cross-Sectional Studies; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Epoxy Compounds; Fatty Acids, Nonesterified; Humans; Lipid Peroxidation; Male; Mice, Inbred C57BL; Middle Aged; Mitochondria; Organophosphorus Compounds; Osteoblasts; Osteogenesis; Reactive Oxygen Species; Toluene; Tumor Suppressor Protein p53; Ubiquinone