Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

Ramila, K. C.; Jong, Chian Ju; Pastukh, Viktor M.; Ito, Takashi; Azuma, Junichi; Schaffer, Stephen W.

doi:10.1152/ajpheart.00497.2014

Cited by 47 publications

(48 citation statements)

References 53 publications

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“…Moreover, the similarity between the actions of rotenone and those of β-alanine [21] implies that β-alanine-mediated reductions in complex I activity also cause a diversion of electrons from complex I to the acceptor oxygen, forming in the process superoxide. Thus, β-alanine treatment is associated with diminished ATP generation and energy metabolism, as well as elevated oxidative stress, factors that are capable of altering the contractile state of the failing heart [28, 29]. These results support the suggestion that β-alanine-mediated oxidative stress contributes to the development of tissue dysfunction, including diminished muscle function and hypotonia.…”

Section: Discussionsupporting

confidence: 57%

“…Figure 5d shows that β-alanine-mediated apoptosis is completely prevented by cyclosporin A, suggesting that activation of the MPT pore is an important contributor to β-alanine-mediated apoptosis. It is interesting that β-alanine exposure reduces the relaxation phase of the Ca 2+ transient, largely by decreasing sarcoplasmic reticular Ca 2+ ATPase activity secondary to diminished phospholamban phosphorylation [28]. These changes in [Ca 2+ ] i may act synergistically with oxidative stress to initiate the mitochondrial permeability transition.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia

et al. 2016

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Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary β-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that β-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing β-alanine. β-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in β-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that β-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as β-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, β-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that β-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia

et al. 2016

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“…Cardiac taurine depletion directly alters the calcium sensitivity of myofibrillar proteins, through impaired sarcoplasmic reticulum calcium ATPase activity and reduced phospholamban phosphorylation. Collectively, these defects yield abnormalities in both systolic and diastolic function (Ramila et al, ). Taurine also acts to attenuate the detrimental effects of catecholamines and angiotensin II in heart failure (Ito et al, ).…”

Section: Discussionmentioning

confidence: 99%

Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non‐targeted metabolomics analysis

Jensen

Parry

Huang

et al. 2017

British J Pharmacology

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“…Not only do damaged mitochondria elevate the risk of cardiomyocyte death, but they also diminish ATP generation and increase ROS production. Recently, Ramila et al (2015) reported that the taurine-deficient cardiomyopathy is also associated with sarcoplasmic reticular Ca 2+ mishandling. The present study raises the possibility that an imbalance in the turnover of proteins, coupled with the accumulation of damaged proteins, may further weaken the TauTKO heart.…”

Section: Discussionmentioning

confidence: 99%

“…Several physiological actions have been attributed to taurine, with metabolic, antioxidant, anti-inflammatory and cytoprotective activities being the most important (Mozaffari et al 1986;Jong et al 2012;Marcinkiewicz and Kontny 2014;Ramila et al 2015). Maintenance of high tissue taurine levels is required for normal cellular function, as taurine deficiency is associated with the development of cardiomyopathy, neuropathy, retinopathy, developmental defects and pregnancy complications (Knopf et al 1978;Sturman et al 1985;Sturman and Messing 1992;Schuller-Levis et al 1990;Ito et al 2008).…”

Section: Introductionmentioning

confidence: 99%

The ubiquitin–proteasome system and autophagy are defective in the taurine-deficient heart

2015

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Taurine depletion leads to impaired mitochondrial function, as characterized by reduced ATP production and elevated superoxide generation. These defects can fundamentally alter cardiomyocyte function and if left unchanged can result in cell death. To protect against these stresses, cardiomyocytes possess quality control processes, such as the ubiquitin-proteasome system (UPS) and autophagy, which can rejuvenate cells through the degradation of damaged proteins and organelles. Hence, the present study tested the hypothesis that reactive oxygen species generated by damaged mitochondria initiates UPS and autophagy in the taurine-deficient heart. Using transgenic mice lacking the taurine transporter (TauTKO) as a model of taurine deficiency, it was shown that the levels of ubiquitinated protein were elevated, an effect associated with a decrease in ATP-dependent 26S β5 proteasome activity. Treating the TauTKO mouse with the mitochondria-specific antioxidant, mitoTEMPO, largely abolished the increase in ubiquitinated protein content. The TauTKO heart was also associated with impaired autophagy, characterized by an increase in the initiator, Beclin-1, and autophagosome content, but a defect in the generation of active autophagolysosomes. Although mitoTEMPO treatment only restores the oxidative balance within the mitochondria, it appeared to completely disrupt the crosstalk between the damaged mitochondria and the quality control processes. Thus, mitochondrial oxidative stress is the main trigger initiating the quality control systems in the taurine-deficient heart. We conclude that the activation of the UPS and autophagy is another fundamental function of mitochondria.

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Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

Abstract: Ramila KC, Jong CJ, Pastukh V, Ito T, Azuma J, Schaffer SW. Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts.

Cited by 47 publications

References 53 publications

Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia

Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia

Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non‐targeted metabolomics analysis

The ubiquitin–proteasome system and autophagy are defective in the taurine-deficient heart

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