Menadione-induced apoptosis: roles of cytosolic Ca2+elevations and the mitochondrial permeability transition pore

Gerasimenko, Julia Vladimirovna; Gerasimenko, Oleg Vsevolodovich; Palejwala, Altaf; Tepikin, Alexei V.; Petersen, Ole H.; Watson, Alistair J. M.

doi:10.1242/jcs.115.3.485

Cited by 145 publications

(18 citation statements)

References 57 publications

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“…This process increases mitochondrial ROS generation, leading to apoptosis by induction of the mitochondrial permeability transition pore complex. 237 Additionally, mitochondrial dysfunction elicits increased ROS generation in the ER. During glucose starvation in yeast (which activates oxidative phosphorylation that occurs in the mitochondria), inactivation or loss of cytochrome-C oxidase (CCO) of the mitochondrial ETC results in upregulation of ROS generation from the surface of the ER.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Redox Signaling by Reactive Electrophiles and Oxidants

et al. 2018

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The concept of cell signaling in the context of nonenzyme-assisted protein modifications by reactive electrophilic and oxidative species, broadly known as redox signaling, is a uniquely complex topic that has been approached from numerous different and multidisciplinary angles. Our Review reflects on five aspects critical for understanding how nature harnesses these noncanonical post-translational modifications to coordinate distinct cellular activities: (1) specific players and their generation, (2) physicochemical properties, (3) mechanisms of action, (4) methods of interrogation, and (5) functional roles in health and disease. Emphasis is primarily placed on the latest progress in the field, but several aspects of classical work likely forgotten/lost are also recollected. For researchers with interests in getting into the field, our Review is anticipated to function as a primer. For the expert, we aim to stimulate thought and discussion about fundamentals of redox signaling mechanisms and nuances of specificity/selectivity and timing in this sophisticated yet fascinating arena at the crossroads of chemistry and biology.

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Section: Chemical Reviewsmentioning

confidence: 99%

Redox Signaling by Reactive Electrophiles and Oxidants

et al. 2018

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“…Earlier studies showed that the oxidant MD induced apoptosis in certain cells . It was also reported that cell death triggered by MD was independent of the apoptotic pathway .…”

Section: Resultsmentioning

confidence: 99%

Menadione‐induced apoptosis in U937 cells involves Bid cleavage and stefin B degradation

Božič

Bidovec

Vizovišek

et al. 2019

J of Cellular Biochemistry

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Earlier studies showed that the oxidant menadione (MD) induces apoptosis in certain cells and also has anticancer effects. Most of these studies emphasized the role of the mitochondria in this process. However, the engagement of other organelles is less known. Particularly, the role of lysosomes and their proteolytic system, which participates in apoptotic cell death, is still unclear. The aim of this study was to investigate the role of lysosomal cathepsins on molecular signaling in MD-induced apoptosis in U937 cells. MD treatment induced translocation of cysteine cathepsins B, C, and S, and aspartic cathepsin D. Once in the cytosol, some cathepsins cleaved the proapoptotic molecule, Bid, in a process that was completely prevented by E64d, a general inhibitor of cysteine cathepsins, and partially prevented by the pancaspase inhibitor, z-VAD-fmk. Upon loss of the mitochondrial membrane potential, apoptosome activation led to caspase-9 processing, activation of caspase-3-like caspases, and poly (ADP-ribose) polymerase cleavage. Notably, the endogenous protein inhibitor, stefin B, was degraded by cathepsin D and caspases. This process was prevented by z-VAD-fmk, and partially by pepstatin A-penetratin.These findings suggest that the cleaved Bid protein acts as an amplifier of apoptotic signaling through mitochondria, thus enhancing the activity of cysteine cathepsins following stefin B degradation. K E Y W O R D S apoptosis, Bid, caspases, cathepsin D, cysteine cathepsins, menadione, stefin B

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“…This event can, in turn, induce redox signaling through the activation of mitochondrial metabolism, further inducing the accumulation of additional H 2 O 2 . This positive feedback mechanism attenuates when Ca 2+ returns from the mitochondrial matrix to the ER [ 66 , 67 ]. This process can be beneficial or detrimental, depending on the cellular context and the levels of ROS generated.…”

Section: Ca 2+ and Oxidative Stressmentioning

confidence: 99%

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

et al. 2022

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Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

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Menadione-induced apoptosis: roles of cytosolic Ca2+elevations and the mitochondrial permeability transition pore

Cited by 145 publications

References 57 publications

Redox Signaling by Reactive Electrophiles and Oxidants

Redox Signaling by Reactive Electrophiles and Oxidants

Menadione‐induced apoptosis in U937 cells involves Bid cleavage and stefin B degradation

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

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