Mitochondrial Fusion Directs Cardiomyocyte Differentiation via Calcineurin and Notch Signaling

Kasahara, Atsuko; Cipolat, Sara; Chen, Yun; Dorn, Gerald W.; Scorrano, Luca

doi:10.1126/science.1241359

Cited by 314 publications

(306 citation statements)

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“…This has been intensified by recognition that Mfn2 may play a critical role in cell‐based therapies promoting the differentiation of stem cells into cardiomyocytes (Kasahara et al, 2013; Suliman et al, 2016). Indeed, DOX‐induced cardiomyopathy is associated with depletion and senescence of the cardiac progenitor cell pool in both rat and human hearts, permanently impairing their function (de Angelis et al, 2010; Piegari et al, 2013).…”

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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“…In this regard, in vivo developmental experiments demonstrated that ablation of cardiac-specific mitochondrial fusion proteins, mitofusin 1 and 2 (MFN1 and MFN2), resulted in an inhibition of mouse heart development. 128 Interestingly, inactivation of Mfn2 or optic atrophy by gene trapping also impaired differentiation of mESCs to cardiomyocytes. 128 Transcriptome analysis of the control and Mfn1-and Mfn2-ablated E9.5 embryos indicated an inhibition of transforming growth factor-β and the transcription factors serum response factor (Srf), Gata4, Nkx.2.5, and myocardin (Myocd), which are essential for cardiomyocyte development.…”

Section: Metabolic Alterations During the Development Of Cardiomyocytesmentioning

confidence: 99%

“…128 Interestingly, inactivation of Mfn2 or optic atrophy by gene trapping also impaired differentiation of mESCs to cardiomyocytes. 128 Transcriptome analysis of the control and Mfn1-and Mfn2-ablated E9.5 embryos indicated an inhibition of transforming growth factor-β and the transcription factors serum response factor (Srf), Gata4, Nkx.2.5, and myocardin (Myocd), which are essential for cardiomyocyte development. 128 This suggests that mitochondrial fusion promotes cardiomyocyte differentiation via calcineurin, intracellular Ca 2+ concentration, and the Notch signaling pathways.…”

Section: Metabolic Alterations During the Development Of Cardiomyocytesmentioning

confidence: 99%

Unique Metabolic Features of Stem Cells, Cardiomyocytes, and Their Progenitors

Gaspar

Doss

Hengstler³

et al. 2014

Circulation Research

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“…Mitochondrial fission, budding off parts of the mitochondrial network, is essential for the identification of dysfunctional and senescent parts of the mitochondrial network and their removal by autophagy [46,73]. In addition, mitochondrial fusion is required for mitochondrial maintenance; it is not only essential for cardiomyocyte differentiation [74], but also for the healthy function of an adult heart [4,75]. However, it is not entirely clear why fragmentation of the mitochondrial network due to impaired fusion has deleterious consequences for the heart, especially as both respiratory chain activity and ATP production are not affected by it [75].…”

Section: Maintenance Of Heart Mitochondrial Homeostasismentioning

confidence: 99%

The role of mitochondria in cardiac development and protection

Pohjoismäki

Goffart

2017

Free Radical Biology and Medicine

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Mitochondria are essential for the development as well as maintenance of the myocardium, the most energy consuming tissue in the human body. Mitochondria are not only a source of ATP energy but also generators of reactive oxygen species (ROS), that cause oxidative damage, but also regulate physiological processes such as the switch from hyperplastic to hypertrophic growth after birth. As excess ROS production and oxidative damage are associated with cardiac pathology, it is not surprising that much of the research focused on the deleterious aspects of free radicals. However, cardiomyocytes are naturally highly adapted against repeating oxidative insults, with evidence suggesting that moderate and acute ROS exposure has beneficial consequences for mitochondrial maintenance and cardiac health. Antioxidant defenses, mitochondrial quality control, mtDNA maintenance mechanisms as well as mitochondrial fusion and fission improve mitochondrial function and cardiomyocyte survival under stress conditions. As these adaptive processes can be induced, promoting mitohormesis or mitochondrial biogenesis using controlled ROS exposure could provide a promising strategy to increase cardiomyocyte survival and prevent pathological remodeling of the myocardium.

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Mitochondrial Fusion Directs Cardiomyocyte Differentiation via Calcineurin and Notch Signaling

Cited by 314 publications

References 28 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

Unique Metabolic Features of Stem Cells, Cardiomyocytes, and Their Progenitors

The role of mitochondria in cardiac development and protection

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