Calcium Signaling Alterations, Oxidative Stress, and Autophagy in Aging

Ureshino, Rodrigo Portes; Rocha, Katiucha K. H. R.; Lopes, Guiomar Silva; Bincoletto, Cláudia; Smaili, Soraya Soubhi

doi:10.1089/ars.2013.5777

Cited by 122 publications

(90 citation statements)

References 199 publications

(173 reference statements)

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“…In particular, excessively high glutamate levels in synaptic terminals leads to calcium overload, which contributes to death during brain aging and in many neurodegenerative conditions. 28 In the rd1 model of retinitis pigmentosa, abnormal calcium accumulation in photoreceptor cells has been linked to cell death independently of cGMP levels. 29 Several studies have also implicated intracellular calcium in autophagy regulation, 30 and the differing outcomes described suggest that calciumdependent autophagy regulation may be both cell-and context-dependent.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

et al. 2014

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Retinitis pigmentosa is a group of hereditary retinal dystrophies that normally result in photoreceptor cell death and vision loss both in animal models and in affected patients. The rd10 mouse, which carries a missense mutation in the Pde6b gene, has been used to characterize the underlying pathophysiology and develop therapies for this devastating and incurable disease. Here we show that increased photoreceptor cell death in the rd10 mouse retina is associated with calcium overload and calpain activation, both of which are observed before the appearance of signs of cell degeneration. These changes are accompanied by an increase in the activity of the lysosomal protease cathepsin B in the cytoplasm of photoreceptor cells, and a reduced colocalization of cathepsin B with lysosomal markers, suggesting that lysosomal membrane permeabilization occurs before the peak of cell death. Moreover, expression of the autophagosomal marker LC3-II (lipidated form of LC3) is reduced and autophagy flux is blocked in rd10 retinas before the onset of photoreceptor cell death. Interestingly, we found that cell death is increased by the induction of autophagy with rapamycin and inhibited by calpain and cathepsin inhibitors, both ex vivo and in vivo. Taken together, these data suggest that calpain-mediated lysosomal membrane permeabilization underlies the lysosomal dysfunction and downregulation of autophagy associated with photoreceptor cell death.

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Section: Discussionmentioning

confidence: 99%

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

et al. 2014

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“…Recent studies indicate that intracellular Ca 2C signaling is involved in autophagy. 100,101 Although it has been suggested that autophagy may be activated by an increase in cytosolic Ca 2C concentration or a perturbed release from intra-or extracellular stores, 100 more compelling evidence has indicated that an increase in intracellular Ca 2C inhibits autophagic flux. [102][103][104] Both mitochondria and the ER play a critical role in Ca 2C homeostasis and regulation of autophagy.…”

Section: Calcium Signaling Intracellular Camentioning

confidence: 99%

Autophagy and ethanol neurotoxicity

Luo

2014

Autophagy

126

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“…In fact, mitochondria are located where high amounts of ATP are required (34) and also where Ca 2 + signaling needs tight regulation (126). Importantly, alterations in mitochondrial Ca 2 + have been related to several pathologies, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) (318), and aging (332). In recent years, it has been demonstrated that mitochondria actively interact with ER membranes through structuredenominated mitochondria-associated membranes, which enable direct and rapid exchange of lipids and Ca 2 + between the two compartments.…”

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confidence: 99%

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Apostolova

Víctor

2015

Antioxidants & Redox Signaling

235

147

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Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid-and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686-729.

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Calcium Signaling Alterations, Oxidative Stress, and Autophagy in Aging

Cited by 122 publications

References 199 publications

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

Autophagy and ethanol neurotoxicity

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

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