Perspectives and Potential Applications of Mitochondria‐Targeted Antioxidants in Cardiometabolic Diseases and Type 2 Diabetes

Rocha, Milagros; Apostolova, Nadezda; Herance, José Raúl; Rovira‐Llopis, Susana; Hernández‐Mijares, Antonio; Víctor, Víctor M.

doi:10.1002/med.21285

Cited by 44 publications

(36 citation statements)

References 187 publications

(210 reference statements)

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“…elevation and increased ROS production trigger mPTP opening, leading to the depletion of ATP and loss of mitochondrial integrity [27,28]. Mitochondria play a key role in cardiac I/R injury by regulating energy homeostasis, and this finding is emerging as a pivotal target in cardiometabolic disease therapy [29]. Previous research has confirmed that cardiac function maintenance is critically dependent on mitochondrial oxidative phosphorylation as a major source of adenosine triphosphate (ATP), and modulating mitochondrial survival/cell-death pathways will subsequently affect cardiomyocyte apoptosis and necrosis [30].…”

Section: Discussionmentioning

confidence: 99%

Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury

Zhang

Wang

et al. 2015

Apoptosis

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Oncostatin M (OSM) exhibits many unique biological activities by activating the Oβ receptor. However, its role in myocardial ischemia/reperfusion injury (I/R injury) in mice remains unknown. We investigated whether Notch3/Akt signaling is involved in the regulation of OSM-induced protection against cardiac I/R injury. The effects of OSM were assessed in mice that underwent myocardial I/R injury by OSM treatment or by genetic deficiency of the OSM receptor Oβ. We investigated its effects on cardiomyocyte apoptosis and mitochondrial biogenesis and whether Notch3/Akt signaling was involved in the regulation of OSM-induced protection against cardiac I/R injury. The mice underwent 30 min of ischemia followed by 3 h of reperfusion and were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) 72 h before coronary artery ligation. Myocardial infarct size, cardiac function, cardiomyocyte apoptosis and mitochondria morphology in mice that underwent cardiac I/R injury were compared between groups. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through promotion of Notch3 production, thus activating the PI3K/Akt pathway. OSM enhanced mitochondrial biogenesis and mitochondrial function in mice subjected to cardiac I/R injury. In contrast, OSM receptor Oβ knock out exacerbated cardiac I/R injury, decreased Notch3 production, enhanced cardiomyocyte apoptosis, and impaired mitochondrial biogenesis in cardiac I/R injured mice. The mechanism of OSM on cardiac I/R injury is partly mediated by the Notch3/Akt pathway. These results suggest a novel role of Notch3/Akt signaling that contributes to OSM-induced protection against cardiac I/R injury.

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Section: Discussionmentioning

confidence: 99%

Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury

Zhang

Wang

et al. 2015

Apoptosis

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“…In this context, an increase of ROS has previously been described in an animal model of anorexia – anx/anx mice [15] - which is in line with our observations of a decrease in O 2 consumption and ΔΨ m and an increase of ROS in human anorexic subjects. High ROS production has been related to the pathology of a high number of diseases, including atherosclerosis, cardiovascular disease, cancer and diabetes [13], [15], [17], [23]–[24]. However, in addition to their status as oxidative molecules, ROS also act as metabolic signalling molecules [25].…”

Section: Discussionmentioning

confidence: 99%

Altered Mitochondrial Function and Oxidative Stress in Leukocytes of Anorexia Nervosa Patients

et al. 2014

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ContextAnorexia nervosa is a common illness among adolescents and is characterised by oxidative stress.ObjectiveThe effects of anorexia on mitochondrial function and redox state in leukocytes from anorexic subjects were evaluated.Design and settingA multi-centre, cross-sectional case-control study was performed.PatientsOur study population consisted of 20 anorexic patients and 20 age-matched controls, all of which were Caucasian women.Main outcome measuresAnthropometric and metabolic parameters were evaluated in the study population. To assess whether anorexia nervosa affects mitochondrial function and redox state in leukocytes of anorexic patients, we measured mitochondrial oxygen consumption, membrane potential, reactive oxygen species production, glutathione levels, mitochondrial mass, and complex I and III activity in polymorphonuclear cells.ResultsMitochondrial function was impaired in the leukocytes of the anorexic patients. This was evident in a decrease in mitochondrial O2 consumption (P<0.05), mitochondrial membrane potential (P<0.01) and GSH levels (P<0.05), and an increase in ROS production (P<0.05) with respect to control subjects. Furthermore, a reduction of mitochondrial mass was detected in leukocytes of the anorexic patients (P<0.05), while the activity of mitochondrial complex I (P<0.001), but not that of complex III, was found to be inhibited in the same population.ConclusionsOxidative stress is produced in the leukocytes of anorexic patients and is closely related to mitochondrial dysfunction. Our results lead us to propose that the oxidative stress that occurs in anorexia takes place at mitochondrial complex I. Future research concerning mitochondrial dysfunction and oxidative stress should aim to determine the physiological mechanism involved in this effect and the physiological impact of anorexia.

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“…25 There are three major isoforms of uncoupling proteins, UCP-1 to -3, which belong to a family of inner mitochondrial membrane proteins that are believed to control several aspects of mitochondrial function, including ROS generation, fatty acid homeostasis, and mitochondrial biogenesis. 26 These isoforms have similarities in structure, but different tissue expressions in mammals. UCP1 is expressed primarily in brown adipose tissue, UCP2 is ubiquitous, and UCP3 is present in skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

Chen

Tang

et al. 2014

Renal Failure

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Renal tubular epithelial cell injury is a major pathological event that contributes to the development of diabetic kidney disease (DKD). Uncoupling protein-2 (UCP2), a mitochondrial membrane protein, has been reported to participate in the regulation of reactive oxygen species (ROS) generation, which contributes to tubular cell apoptosis induced by hyperglycemia. In this study, we found that genipin, a UCP2 inhibitor, dramatically boosted oxidative stress, attenuated antioxidative capacity, and exacerbated cell apoptosis accompanied with caspase-3 activation in rat renal proximal tubular cells (NRK-52E) incubated with high glucose. The present study results suggest that manipulation of UCP2 could be important in the prevention of oxidative stress damage in renal tubular epithelial cells induced by hyperglycemia in vitro.

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Perspectives and Potential Applications of Mitochondria‐Targeted Antioxidants in Cardiometabolic Diseases and Type 2 Diabetes

Cited by 44 publications

References 187 publications

Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury

Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury

Altered Mitochondrial Function and Oxidative Stress in Leukocytes of Anorexia Nervosa Patients

Downregulation of uncoupling protein-2 by genipin exacerbates diabetes-induced kidney proximal tubular cells apoptosis

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