Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy

Pedrozo, Zully; Torrealba, Natalia; Fernández, Carolina; Gatica, Damián; Toro, Barbra; Quiroga, Clara; Rodríguez, Andrea; Pecchi, Gina; Gillette, Thomas G.; Hill, Joseph A.; Donoso, P; Lavandero, Sergio

doi:10.1093/cvr/cvt029

Cited by 52 publications

(36 citation statements)

References 32 publications

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“…The activation of these proteases was evaluated by determining the cleavage of pro-caspase 3 to active caspase-3 and of α-spectrin, an important target of activated calpains [34]. As shown in the Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death

Parra

Moraga

Kuzmicic

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Ceramides are important intermediates in the biosynthesis and degradation of sphingolipids that regulatenumerous cellular processes, including cell cycle progression, cell growth, differentiation and death. In cardiomyocytes, ceramides induce apoptosis by decreasing mitochondrial membrane potential and promoting cytochrome-c release. Ca2+ overload is a common feature of all types of cell death. The aim of this study was to determine the effect of ceramides on cytoplasmic Ca2+ levels, mitochondrial function and cardiomyocyte death. Our data show that C2-ceramide induces apoptosis and necrosis in cultured cardiomyocytes by a mechanism involving increased Ca2+ influx, mitochondrial network fragmentation and loss of the mitochondrial Ca2+ buffer capacity. These biochemical events increase cytosolic Ca2+ levels and trigger cardiomyocyte death via the activation of calpains.

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Section: Resultsmentioning

confidence: 99%

Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death

Parra

Moraga

Kuzmicic

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In the absence of LAMP-2, fusion of autophagosomes with lysosomes is blocked leading to accumulation of long-lived proteins, ultimately resulting in myopathy. Recent studies by Pedrozo et al (2013) demonstrated that the ryanodine receptor type 2 (RyR2), the main cardiac sarcoplasmic reticulum calcium-release channel required for cardiomyocyte excitation-contraction and often associated with myocardial remodeling after ischemia/reperfusion (I/R) and cardiac failure, is degraded by CMA. Furthermore, the authors demonstrated that CMA-mediated degradation of RyR2 induced by oxidative stress depends on presenilins (Pedrozo et al, 2013).…”

Section: Ubiquitin Autophagy and The Heartmentioning

confidence: 99%

Autophagy and Ubiquitination in Cardiovascular Diseases

Martins‐Marques

Ribeiro-Rodrigues

Pereira

et al. 2015

DNA and Cell Biology

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A main function of the heart is to pump blood to the tissues and organs of the body. Although formed by different types of cells, the cardiomyocytes are the ones responsible for the coordinated and synchronized heart contraction. Given their low mitotic activity, cardiomyocytes largely depend on protein degradation mechanisms to maintain proteostasis and energetic balance. Autophagy, one of the main pathways whereby cells eliminate damaged, nonfunctional, or obsolete proteins, and organelles, is vital to ensure cell function, including in cardiomyocytes, both in rest and stress conditions. However, the impact of autophagy activation in the heart, being either protective or harmful, is not consensual and likely depends upon the severity of the stimuli and consequently the autophagy players involved. One of the signals that direct proteins for autophagy degradation, namely in the context of heart disorders, is ubiquitin. Indeed, the attachment of ubiquitin moieties to a target substrate and further recognition by autophagy adaptors constitute a main regulatory pathway that directs proteins to the lysosome. Therefore, a better understanding of the mechanisms and signals that regulate the autophagy process in the heart, including substrates targeting, is of utmost importance to design new approaches directed to this degradation pathway. We have previously shown that ubiquitination of the gap junction (GJ) protein Connexin43 (Cx43) triggers its degradation by autophagy through a process that requires the ubiquitin adaptors epidermal growth factor receptor substrate 15 (Eps15) and p62. This is particularly relevant in the heart because GJs, that form intercellular channels, are responsible for the rapid and efficient anisotropic propagation of the electrical impulse through the cardiomyocytes, essential for synchronized contraction of the cardiac muscle. In this review, we present recent studies devoted to the involvement of autophagy in heart homeostasis, with a particular focus on ubiquitin and GJs.

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“…Interestingly we recently discovered that RYR2 (ryanodine receptor 2 [cardiac]) sequence harbors six KFERQ motifs, and is degraded via chaperone-mediated autophagy. 35 As RYR2 plays a key role in cardiomyocyte excitation-contraction and its dysfunction can contribute to cardiac failure, this observation may have pathophysiological relevance.…”

Section: Autophagymentioning

confidence: 99%

Cardiovascular autophagy

et al. 2013

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Despite recent scientific and technological advances, cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of heart pathologies. However, the precise role of autophagy in these contexts remains obscure owing to its multifarious actions. Here, we review recently derived insights regarding the role of autophagy in multiple manifestations of cardiac plasticity and disease.

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Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy

Abstract: These findings are consistent with a model in which oxidative damage of the RyR2 targets it for turnover by presenilins and CMA, which could lead to removal of damaged or leaky RyR2 channels.

Cited by 52 publications

References 32 publications

Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death

Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death

Autophagy and Ubiquitination in Cardiovascular Diseases

Cardiovascular autophagy

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