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      Melatonin Attenuates Cardiac Reperfusion Stress by Improving OPA1-Related Mitochondrial Fusion in a Yap–Hippo Pathway–Dependent Manner

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          Abstract:

          The role of OPA1-related mitochondrial fusion in cardiac reperfusion stress has remained elusive. The aim of our study is to explore whether melatonin alleviates cardiac ischemia-reperfusion (IR) injury by modulating OPA1-related mitochondrial fusion. We found that melatonin reduced infarct area, sustained myocardial function, and suppressed cardiomyocyte death during cardiac reperfusion stress. Biological studies have revealed that IR-inhibited mitochondrial fusion was largely reversed by melatonin through upregulated OPA1 expression. Knocking down OPA1 abrogated the protective effects of melatonin on mitochondrial energy metabolism and mitochondrial apoptosis. In addition, we also found that melatonin modified OPA1 expression through the Yap–Hippo pathway; blockade of the Yap–Hippo pathway induced cardiomyocyte death and mitochondrial damage despite treatment with melatonin. Altogether, our data demonstrated that cardiac IR injury is closely associated with defective OPA1-related mitochondrial fusion. Melatonin supplementation enhances OPA1-related mitochondrial fusion by activating the Yap–Hippo pathway, ultimately reducing cardiac reperfusion stress.

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          Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration

          Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD.
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            Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2α-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy

            Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2α CKO ) mice were protected against IR injury and mitochondrial damage. Functional assay indicated that CK2α enhanced the phosphorylation (inactivation) of FUN14 domain containing 1 (FUNDC1) via post-transcriptional modification at Ser13, thus effectively inhibiting mitophagy. Defective mitophagy failed to remove damaged mitochondria induced by IR injury, resulting in mitochondrial genome collapse, electron transport chain complex (ETC) inhibition, mitochondrial biogenesis arrest, cardiolipin oxidation, oxidative stress, mPTP opening, mitochondrial debris accumulation and eventually mitochondrial apoptosis. In contrast, loss of CK2α reversed the FUNDC1-mediated mitophagy, providing a survival advantage to myocardial tissue following IR stress. Interestingly, mice deficient in both CK2α and FUNDC1 failed to show protection against IR injury and mitochondrial damage through a mechanism possible attributed to lack of mitophagy. Taken together, our results confirmed that CK2α serves as a negative regulator of mitochondrial homeostasis via suppression of FUNDC1-required mitophagy, favoring the development of cardiac IR injury.
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              Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission‐VDAC1‐HK2‐mPTP‐mitophagy axis

              Abstract The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury (IRI) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells (CMEC) in melatonin‐treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP‐activated protein kinase α (AMPKα) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission, which subsequently induced voltage‐dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy‐mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPKα, followed by p‐Drp1S616 downregulation and p‐Drp1S37 upregulation, which blunted Drp1‐dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC1‐HK2 interaction that prevented mPTP opening and PINK1/Parkin activation, eventually blocking mitophagy‐mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI. The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission‐VDAC1‐HK2‐mPTP‐mitophagy axis via activation of AMPKα.
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                Author and article information

                Journal
                J Cardiovasc Pharmacol
                J. Cardiovasc. Pharmacol
                jcvp
                Journal of Cardiovascular Pharmacology
                Journal of Cardiovascular Pharmacology
                0160-2446
                1533-4023
                January 2019
                04 December 2018
                : 73
                : 1
                : 27-39
                Affiliations
                Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
                Author notes
                Reprints: Zhenming Dong, Department of Anesthesiology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, China (e-mail: hbdzmxx@ 123456126.com ).
                Article
                JCVP-18-424 00005
                10.1097/FJC.0000000000000626
                6319588
                30418242
                0d8ec6d5-db6b-4fda-8383-d9aa17e10dca
                Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 06 September 2018
                : 02 October 2018
                Categories
                Original Article
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                melatonin,opa1,mitochondrial fusion,yap–hippo pathway,reperfusion stress

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