Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury

Ong, Sang‐Bing; Subrayan, Sapna; Lim, Shiang Y.; Yellon, Derek M.; Davidson, Sean M.; Hausenloy, Derek J.

doi:10.1161/circulationaha.109.906610

Cited by 856 publications

(895 citation statements)

References 29 publications

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“…Loss of Mfn2 also delayed membrane depolarization in isolated cardiomyocytes from adult Mfn2 −/− mice, leading to the suggestion that Mfn2 may function to control mitochondrial permeability transition pore opening (Papanicolaou et al, 2011). Similarly, cardiac‐specific deletion of Mfn2 produced dissipation of mitochondrial membrane potential and elevated ROS production (Chen et al, 2012), whilst overexpression of Mfn2 was found to increase the percentage of cells containing elongated mitochondria, thereby reducing mitochondrial permeability transition pore opening and cell death after simulated ischaemia/reperfusion injury (Ong et al, 2010). It also appears that Mfn2 serves an essential role in maintaining mitochondrial coenzyme Q levels in mouse hearts, thereby promoting optimal function of the respiratory chain (Mourier et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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Background and PurposeThe anthracycline doxorubicin (DOX), although successful as a first‐line cancer treatment, induces cardiotoxicity linked with increased production of myocardial ROS, with Nox2 NADPH oxidase‐derived superoxide reported to play a key role. The aim of this study was to identify novel mechanisms underlying development of cardiac remodelling/dysfunction further to DOX‐stimulated Nox2 activation.Experimental ApproachNox2−/− and wild‐type (WT) littermate mice were administered DOX (12 mg·kg−1 over 3 weeks) prior to study at 4 weeks. Detailed mechanisms were investigated in murine HL‐1 cardiomyocytes, employing a robust model of oxidative stress, gene silencing and pharmacological tools.Key ResultsDOX‐induced cardiac dysfunction, cardiomyocyte remodelling, superoxide production and apoptosis in WT mice were attenuated in Nox2−/− mice. Transcriptional analysis of left ventricular tissue identified 152 differentially regulated genes (using adjusted P < 0.1) in DOX‐treated Nox2−/− versus WT mice, and network analysis highlighted ‘Cell death and survival’ as the biological function most significant to the dataset. The mitochondrial membrane protein, mitofusin‐2 (Mfn2), appeared as a strong candidate, with increased expression (1.5‐fold), confirmed by qPCR (1.3‐fold), matching clear published evidence of promotion of cardiomyocyte cell death. In HL‐1 cardiomyocytes, targeted siRNA knockdown of Nox2 decreased Mfn2 protein expression, but not vice versa. While inhibition of Nox2 activity along with DOX treatment attenuated its apoptotic and cytotoxic effects, reduced apoptosis after Mfn2 silencing reflected a sustained cytotoxic response and reduced cell viability.Conclusions and ImplicationsDOX‐induced and Nox2‐mediated up‐regulation of Mfn2, rather than contributing to cardiomyocyte dysfunction through apoptotic pathways, appears to promote a protective mechanism.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Discussionmentioning

confidence: 99%

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

McLaughlin

Zhao

O’Neill

et al. 2017

British J Pharmacology

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“…10b, upper panel) and apoptosis ( Supplementary Fig. 10b, lower ARTICLE and heart failure 6,7 . Thus, it is necessary to elucidate the molecular mechanisms of mitochondrial regulation, and discover potential therapeutic targets for inhibiting myocardial infarction and the consequent heart failure.…”

Section: Pink1 Inhibits Mitochondrial Fragmentation and Apoptosismentioning

confidence: 99%

“…For example, knockdown of Drp1 inhibits mitochondrial fragmentation and p53-dependent apoptosis 7,37 . Enforced expression of Mfn2 leads to mitochondrial fusion that is important for cell survival 38 .…”

Section: Pink1 Inhibits Mitochondrial Fragmentation and Apoptosismentioning

confidence: 99%

“…Fission leads to the formation of small round mitochondria and promotes cell apoptosis, whereas fusion results in mitochondria elongation and plays a protective role in cardiomyocytes maintenance 5 . Although emerging evidences demonstrate that mitochondrial fission and fusion machinery are important for maintaining cardiac function [6][7][8] , little work suggests the transcriptional control of mitochondrial network regulators. And unveiling the mechanism of mitochondrial network regulation will provide a novel therapeutic strategy for heart failure.…”

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confidence: 99%

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E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Wang

Zhou

et al. 2015

Nat Commun

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Mitochondrial fragmentation plays an important role in the progression of cardiac diseases, such as myocardial infarction and heart failure. Mitochondrial network is controlled by many factors in different cell types. Here we show that the interplay between E2F1, miR-421 and Pink1 regulates mitochondrial morphology and cardiomyocyte cell death. Pink1 reduces mitochondrial fragmentation and protects cardiomyocyte from apoptosis. On the other hand, miR-421 promotes cardiomyocyte mitochondrial fragmentation, apoptosis and myocardial infarction by suppressing Pink1 translation. Finally, we show that transcription factor E2F1 activates miR-421 expression. Knocking down E2F1 suppresses mitochondrial fragmentation, apoptosis and myocardial infarction by affecting miR-421 levels. Collectively, these data identify the E2F1/miR-421/Pink axis as a regulator of mitochondrial fragmentation and cardiomyocyte apoptosis, and suggest potential therapeutic targets in treatment of cardiac diseases.

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“…In a variety of cardiac diseases, mitochondria exhibit the abnormal morphology with a small size and fragmentation because of excess fission (Schaper et al, 1991;Hom and Sheu, 2009). A recent research demonstrates that the pharmacological inhibition of the mitochondrial fission protein Drp1 can protect adult murine cardiomyocytes against ischemia/reperfusion injury and reduce myocardial infarct size in the murine heart (Ong et al, 2010). Another research reveals that mitochondria in the neonatal and adult cardiomyocytes undergo rapid and transient fragmentation in response to thapsigargin-or KCl-induced cytosolic calcium increase (Hom et al, 2010).…”

Section: Mitochondria and Heart Diseasesmentioning

confidence: 99%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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Mitochondria are subcellular organelles that provide energy for the cell. They form a dynamic tubular network and play an important role in maintaining the cell function and integrity. Heart is a powerful organ that supplies the motivation for circulation, thereby requiring large amounts of energy. Thus, the healthiness of cardiomyocytes and mitochondria is necessary for the normal cardiac function. Mitochondria not only lie in the center of the cell apoptotic pathway, but also are the major source of reactive oxygen species (ROS) generation. Mitochondrial morphological change includes fission and fusion that are regulated by a large number of proteins. In this review we discuss the regulators of mitochondrial fission/fusion and their association with cell apoptosis, autophagy and ROS production in the heart.

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Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury

Cited by 856 publications

References 29 publications

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Mitochondrial network in the heart

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