Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury

Olmedo, Ivonne; Pino, G Nidia; Riquelme, Jaime A.; Aránguiz, Pablo; Díaz, Magda C.; López-Crisosto, Camila; Lavandero, Sergio; Donoso, P; Pedrozo, Zully; Pecchi, Gina

doi:10.1016/j.bbadis.2019.165659

Cited by 17 publications

(14 citation statements)

References 68 publications

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“…The mitochondrial protease, LonP1, which contributes to mitochondrial proteostasis and regulates adaptive responses to cell stress, has been shown to contribute to the cardioprotection elicited by ischaemic preconditioning [59] . The ubiquitin-proteasome system (UPS) eliminates misfolded or damaged proteins in the heart via selective polyubiquitination and subsequent degradation by the proteasome, and pharmacological inhibition of the proteasome, using MG132, has been shown to protect the isolated perfused rat heart against acute myocardial IRI by preserving myocardial Mfn2 levels, maintaining mitochondrial mass, and inhibiting mitochondrial fission [60] .…”

Section: Targeting Mitochondrial Fission and Fusion Proteins For Cardmentioning

confidence: 99%

Mitochondria in acute myocardial infarction and cardioprotection

et al. 2020

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Acute myocardial infarction (AMI) and the heart failure (HF) that often follows are among the leading causes of death and disability worldwide. As such, new treatments are needed to protect the myocardium against the damaging effects of the acute ischaemia and reperfusion injury (IRI) that occurs in AMI, in order to reduce myocardial infarct (MI) size, preserve cardiac function, and improve patient outcomes. In this regard, cardiac mitochondria play a dual role as arbiters of cell survival and death following AMI. Therefore, preventing mitochondrial dysfunction induced by acute myocardial IRI is an important therapeutic strategy for cardioprotection. In this article, we review the role of mitochondria as key determinants of acute myocardial IRI, and we highlight their roles as therapeutic targets for reducing MI size and preventing HF following AMI. In addition, we discuss the challenges in translating mitoprotective strategies into the clinical setting for improving outcomes in AMI patients.

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Section: Targeting Mitochondrial Fission and Fusion Proteins For Cardmentioning

confidence: 99%

Mitochondria in acute myocardial infarction and cardioprotection

et al. 2020

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“…In contrast, Olmedo et al 55 found that MG132, a proteasome inhibitor which can inhibit the degradation of Mfn2, or the overexpression of Mfn2 could lessen the broken mitochondrial network of cardiomyocytes and promote mitochondrial fusion. 32,55 In summary, Mfn is a cardiac protective factor and accelerating the level of Mfn after MI is conducive to improving heart function. However, recent studies indicated that short-term knockout of Mfn1/2 can increase mitochondrial resistance to MPTP opening during MI, reduce calcium overload and oxidative stress and protect the heart from MI.…”

Section: Mitochondrial Fusion After MImentioning

confidence: 88%

“…These findings suggested that the abnormal expression of Mfn might be related to a decrease in mitochondrial fusion after MI. In contrast, Olmedo et al 55 found that MG132, a proteasome inhibitor which can inhibit the degradation of Mfn2, or the overexpression of Mfn2 could lessen the broken mitochondrial network of cardiomyocytes and promote mitochondrial fusion 32,55 . In summary, Mfn is a cardiac protective factor and accelerating the level of Mfn after MI is conducive to improving heart function.…”

Section: Cardiac Mitochondrial Dynamics: Fission/fusionmentioning

confidence: 93%

Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction

Wang

Liu

Wang

et al. 2021

J Cellular Molecular Medi

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Mitochondria are important organelles in eukaryotic cells. Normal mitochondrial homeostasis is subject to a strict mitochondrial quality control system, including the strict regulation of mitochondrial production, fission/fusion and mitophagy. The strict and accurate modulation of the mitochondrial quality control system, comprising the mitochondrial fission/fusion, mitophagy and other processes, can ameliorate the myocardial injury of myocardial ischaemia and ischaemia‐reperfusion after myocardial infarction, which plays an important role in myocardial protection after myocardial infarction. Further research into the mechanism will help identify new therapeutic targets and drugs for the treatment of myocardial infarction. This article aims to summarize the recent research regarding the mitochondrial quality control system and its molecular mechanism involved in myocardial infarction, as well as the potential therapeutic targets in the future.

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“…For instance, proteasome inhibition is generally considered harmful to cardiac functions. However, evidence also exists implicating proteasome inhibition in prevention and reversal of maladaptive hypertrophy and cardiac remodeling 40 , 46 , 47 . Several studies have suggested that the controversy could be due to the extent of proteasome inhibition or its effects on noncardiomyocyte compartment 5 , 48 .…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition

et al. 2020

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Heart is a multi-cellular organ made up of various cell types interacting with each other. Cardiomyocytes may benefit or suffer from crosstalk with noncardiomyocytes in response to diverse kinds of cardiac stresses. Proteasome dysfunction is a common cardiac stress which causes cardiac proteotoxicity and contributes to cardiac diseases such as heart failure and myocardial infarction. The role of crosstalk between cardiomyocytes and noncardiomyocytes in defense of cardiac proteotoxicity remains unknown. Here, we report a cardiomyocyte-specific survival upon proteasome inhibition in a heterogeneous culture consisting of cardiomyocytes and other three major cardiac cell types. Conversely, cardiomyocyte apoptosis is remarkably induced by proteasome inhibition in a homogeneous culture consisting of a majority of cardiomyocytes, demonstrating an indispensable role of noncardiomyocytes in the prevention of cardiomyocyte apoptosis resulting from proteasome inhibition. We further show that cardiomyocytes express brain natriuretic peptide (BNP) as an extracellular molecule in response to proteasome inhibition. Blockade of BNP receptor on noncardiomyocytes significantly exacerbated the cardiomyocyte apoptosis, indicating a paracrine function of cardiomyocyte-released extracellular BNP in activation of a protective feedback from noncardiomyocytes. Finally, we demonstrate that proteasome inhibition-activated transcriptional up-regulation of BNP in cardiomyocytes was associated with the dissociation of repressor element 1 silencing transcription factor (REST)/ histone deacetylase 1 (HDAC1) repressor complex from BNP gene promoter. Consistently, the induction of BNP could be further augmented by the treatment of HDAC inhibitors. We conclude that the crosstalk between cardiomyocytes and noncardiomyocytes plays a crucial role in the protection of cardiomyocytes from proteotoxicity stress, and identify cardiomyocyte-released BNP as a novel paracrine signaling molecule mediating this crosstalk. These findings provide new insights into the key regulators and cardioprotective mechanism in proteasome dysfunction-related cardiac diseases.

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Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury

Cited by 17 publications

References 68 publications

Mitochondria in acute myocardial infarction and cardioprotection

Mitochondria in acute myocardial infarction and cardioprotection

Advances in the mechanism and treatment of mitochondrial quality control involved in myocardial infarction

Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition

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