The FGF-2-triggered protection of cardiac subsarcolemmal mitochondria from calcium overload is mitochondrial connexin 43-dependent

Srisakuldee, Wattamon; Makazan, Zhanna; Nickel, Barbara E.; Zhang, Feixiong; Thliveris, James A.; Pasumarthi, Kishore B.S.; Kardami, Elissavet

doi:10.1093/cvr/cvu066

Cited by 63 publications

(67 citation statements)

References 52 publications

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“…A notion that may explain differences between studies is the possibility that different mitophagy receptors could target different mitochondrial populations within the myocytes. Adult cardiomyocytes possess subsarcolemmal (SSM) and interfibrillar mitochondria (IFM), with distinct morphological and functional properties as well as distinct sensitivities to calcium overload [125]. There is currently limited information regarding how these different mitochondrial populations may be targeted for mitophagy, before or after Dox.…”

Section: Dox and The Autophagy Processmentioning

confidence: 99%

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

2017

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Doxorubicin (Dox) is a cytotoxic drug widely incorporated in various chemotherapy protocols. Severe side effects such as cardiotoxicity, however, limit Dox application. Mechanisms by which Dox promotes cardiac damage and cardiomyocyte cell death have been investigated extensively, but a definitive picture has yet to emerge. Autophagy, regarded generally as a protective mechanism that maintains cell viability by recycling unwanted and damaged cellular constituents, is nevertheless subject to dysregulation having detrimental effects for the cell. Autophagic cell death has been described, and has been proposed to contribute to Dox-cardiotoxicity. Additionally, mitophagy, autophagic removal of damaged mitochondria, is affected by Dox in a manner contributing to toxicity. Here we will review Dox-induced cardiotoxicity and cell death in the broad context of the autophagy and mitophagy processes.

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Section: Dox and The Autophagy Processmentioning

confidence: 99%

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

2017

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“…Regulation of the matrix calcium content also depends on mitochondrial Cx43; the calcium retention capacity of subsarcolemmal mitochondria was reduced by blocking Cx43-formed channels with Gap27 (Srisakuldee et al, 2014). In mitochondria derived from rat brain, carbenoxolone reduced the calcium retention capacity (Azarashvili et al, 2011).…”

Section: Mitochondrial CX 43mentioning

confidence: 99%

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

Schulz

Görge

Görbe

et al. 2015

Pharmacology & Therapeutics

194

174

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Connexins are widely distributed proteins in the body that are crucially important for heart and brain function. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localisation at the sarcolemma of cardiomyocytes and brain cells, connexins are also found in mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodelling or heart failure, and post-translationally connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injury as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissue following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection.

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“…Aside from disease-or mutation-associated mislocalization, the possibility that connexins could be localized to and function at cellular locations other than the plasma membrane is an exciting concept (Figure 1, lower panel). Cx43 has been localized to the inner membrane of myocardial subsarcolemmal mitochondria (SSM) of cardiomyocytes where it plays a role in ischemic preconditioning during ischemia-reperfusion injury [21,[68][69][70][71][72][73][74][75][76][77][78][79][80][81]. Ischemic preconditioning of cardiac myocytes in rodent hearts increases Cx43 occupancy, phosphorylation and S-nitrosylation at the inner SSM, and knocking out or blocking Cx43 in the myocardium decreased the effectiveness of pharmacologically protective agents of ischemia-reperfusion injury [21,[68][69][70][71][72][73][74][75][76][77][78][79][80][81].…”

Section: Connexin and Pannexin Localization In Unexpected Organelles mentioning

confidence: 99%

Next-Generation Connexin and Pannexin Cell Biology

Esseltine

Laird

2016

Trends in Cell Biology

114

107

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The FGF-2-triggered protection of cardiac subsarcolemmal mitochondria from calcium overload is mitochondrial connexin 43-dependent

Abstract: SSM are more responsive than IFM to FGF-2-triggered protection from calcium-induced mPTP, by a mitochondrial Cx43 channel-mediated pathway, associated with mitochondrial Cx43 phosphorylation at PKCε target sites.

Cited by 63 publications

References 52 publications

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

Next-Generation Connexin and Pannexin Cell Biology

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