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Open AccessEditorial

Crosstalk of Autophagy and Apoptosis

by Maurizio Sorice

Cells 2022, 11(9), 1479; https://doi.org/10.3390/cells11091479 - 28 Apr 2022

Cited by 91 | Viewed by 5963

Abstract

Autophagy and apoptosis represent two fundamental pathophysiological mechanisms of cell fate regulation. However, the signaling pathways of these processes are significantly interconnected through various mechanisms of crosstalk. Indeed, autophagy/apoptosis crosstalk is still an emerging field, in which an increasing number of molecules are [...] Read more.

Autophagy and apoptosis represent two fundamental pathophysiological mechanisms of cell fate regulation. However, the signaling pathways of these processes are significantly interconnected through various mechanisms of crosstalk. Indeed, autophagy/apoptosis crosstalk is still an emerging field, in which an increasing number of molecules are involved, including, for example, PINK1 and ERLINs. On the other hand, this crosstalk involves signal transduction pathways which are strongly dependent on Ca²⁺. Interestingly, crosstalk between autophagy and apoptosis impacts several pathologies, including multiple rheumatic diseases. The purpose of this Special Issue is also to investigate the bioactive properties of drugs with antitumor activity, focusing particularly on the role of anthraquinone derivatives in the regulation of cell death and autophagy crosstalk. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of crosstalk between autophagy and apoptosis and the interconnected signaling pathways, implying therapeutic perspectives for the utility of its modulation in an anti-cancer setting. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

Research

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15 pages, 3146 KiB

Open AccessArticle

PINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage

by Francesco Brunelli, Liliana Torosantucci, Vania Gelmetti, Davide Franzone, Anne Grünewald, Rejko Krüger, Giuseppe Arena and Enza Maria Valente

Cells 2022, 11(4), 678; https://doi.org/10.3390/cells11040678 - 15 Feb 2022

Cited by 10 | Viewed by 3514

Abstract

PINK1 is a causative gene for Parkinson’s disease and the corresponding protein has been identified as a master regulator of mitophagy—the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. [...] Read more.

PINK1 is a causative gene for Parkinson’s disease and the corresponding protein has been identified as a master regulator of mitophagy—the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson’s disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the pro-apoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1–Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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15 pages, 2491 KiB

Open AccessArticle

In Vitro Anticancer Screening and Preliminary Mechanistic Study of A-Ring Substituted Anthraquinone Derivatives

by Ibrahim Morgan, Ludger A. Wessjohann and Goran N. Kaluđerović

Cells 2022, 11(1), 168; https://doi.org/10.3390/cells11010168 - 5 Jan 2022

Cited by 14 | Viewed by 3245

Abstract

Anthraquinone derivatives exhibit various biological activities, e.g., antifungal, antibacterial and in vitro antiviral activities. They are naturally produced in many fungal and plant families such as Rhamnaceae or Fabaceae. Furthermore, they were found to have anticancer activity, exemplified by mitoxantrone and pixantrone, and [...] Read more.

Anthraquinone derivatives exhibit various biological activities, e.g., antifungal, antibacterial and in vitro antiviral activities. They are naturally produced in many fungal and plant families such as Rhamnaceae or Fabaceae. Furthermore, they were found to have anticancer activity, exemplified by mitoxantrone and pixantrone, and many are well known redox-active compounds. In this study, various nature inspired synthetic anthraquinone derivatives were tested against colon, prostate, liver and cervical cancer cell lines. Most of the compounds exhibit anticancer effects against all cell lines, therefore the compounds were further studied to determine their IC₅₀-values. Of these compounds, 1,4-bis(benzyloxy)-2,3-bis(hydroxymethyl)anthracene-9,10-dione (4) exhibited the highest cytotoxicity against PC3 cells and was chosen for a deeper look into its mechanism of action. Based on flow cytometry, the compound was proven to induce apoptosis through the activation of caspases and to demolish the ROS/RNS and NO equilibrium in the PC3 cell line. It trapped cells in the G2/M phase. Western blotting was performed for several proteins related to the effects observed. Compound 4 enhanced the production of PARP and caspase-3. Moreover, it activated the conversion of LC3A/B-I to LC3A/B-II showing that also autophagy plays a role in its mechanism of action, and it caused the phosphorylation of p70 s6 kinase. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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15 pages, 6216 KiB

Open AccessArticle

Physcion Induces Potential Anticancer Effects in Cervical Cancer Cells

by Wojciech Trybus, Teodora Król, Ewa Trybus and Anna Stachurska

Cells 2021, 10(8), 2029; https://doi.org/10.3390/cells10082029 - 8 Aug 2021

Cited by 20 | Viewed by 3004

Abstract

Background: The extent of morphological and ultrastructural changes in HeLa cells was assessed by optical, fluorescence and electron microscopy after exposure to various concentrations of physcion, taking into account the biological properties of the test compound. Methods: Cell viability was assessed by MTT [...] Read more.

Background: The extent of morphological and ultrastructural changes in HeLa cells was assessed by optical, fluorescence and electron microscopy after exposure to various concentrations of physcion, taking into account the biological properties of the test compound. Methods: Cell viability was assessed by MTT assay, while the cell cycle, LC3 expression, apoptosis, change of mitochondrial potential, Bcl-2 protein expression level and the level of reactive oxygen species were analyzed by flow cytometry. Results: As a result of physcion encumbrance, concentration-dependent inhibition of HeLa cell viability and the G0/G1 phase of the cell cycle was observed. Activation of the lysosomal system was also revealed, which was expressed by an increased number of lysosomes, autophage vacuoles and increased expression of the LC3 protein, a marker of the autophagy process. Transmission electron microscopy and fluorescence microscopy showed that physcion induced clear changes in cervical cancer cells, especially in the structure of the nucleus and mitochondria, which correlated with the production of reactive oxygen species by the test compound and indicated the induction of the oxidative process. At the same time, the pro-apoptotic effect of physcion was demonstrated, and this mechanism was dependent on the activation of caspases 3/7 and the reduction in Bcl-2 protein expression. Conclusion: The obtained results indicate an antitumor mechanism of action of physcion, based on the induction of oxidative stress, autophagy and apoptosis. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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14 pages, 4163 KiB

Open AccessArticle

BNIP3-Dependent Mitophagy via PGC1α Promotes Cartilage Degradation

by Deokha Kim, Jinsoo Song and Eun-Jung Jin

Cells 2021, 10(7), 1839; https://doi.org/10.3390/cells10071839 - 20 Jul 2021

Cited by 28 | Viewed by 4739

Abstract

Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA [...] Read more.

Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA pathogenesis and identified the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α) as a potent regulator. The expression level of PGC1α was significantly decreased under OA conditions, and knockdown of PGC1α dramatically elevated the cartilage degradation by upregulating cartilage degrading enzymes and apoptotic cell death. Interestingly, the knockdown of PGC1α activated the parkin RBR E3 ubiquitin protein ligase (PRKN)-independent selective mitochondria autophagy (mitophagy) pathway through the upregulation of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). The overexpression of BNIP3 stimulated mitophagy and cartilage degradation by upregulating cartilage-degrading enzymes and chondrocyte death. We identified microRNA (miR)-126-5p as an upstream regulator for PGC1α and confirmed the direct binding between miR-126-5p and 3′ untranslated region (UTR) of PGC1α. An in vivo OA mouse model induced by the destabilization of medial meniscus (DMM) surgery, and the delivery of antago-miR-126 via intra-articular injection significantly decreased cartilage degradation. In sum, the loss of PGC1α in chondrocytes due to upregulation of miR-126-5p during OA pathogenesis resulted in the activation of PRKN-independent mitophagy through the upregulation of BNIP3 and stimulated cartilage degradation and apoptotic death of chondrocytes. Therefore, the regulation of PGC1α:BNIP3 mitophagy axis could be of therapeutic benefit to cartilage-degrading diseases. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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Review

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9 pages, 1202 KiB

Open AccessReview

Autophagy in Rheumatic Diseases: Role in the Pathogenesis and Therapeutic Approaches

by Alessandra Ida Celia, Serena Colafrancesco, Cristiana Barbati, Cristiano Alessandri and Fabrizio Conti

Cells 2022, 11(8), 1359; https://doi.org/10.3390/cells11081359 - 15 Apr 2022

Cited by 15 | Viewed by 3390

Abstract

Autophagy is a lysosomal pathway for the degradation of damaged proteins and intracellular components that promotes cell survival under specific conditions. Apoptosis is, in contrast, a critical programmed cell death mechanism, and the relationship between these two processes influences cell fate. Recent evidence [...] Read more.

Autophagy is a lysosomal pathway for the degradation of damaged proteins and intracellular components that promotes cell survival under specific conditions. Apoptosis is, in contrast, a critical programmed cell death mechanism, and the relationship between these two processes influences cell fate. Recent evidence suggests that autophagy and apoptosis are involved in the self-tolerance promotion and in the regulatory mechanisms contributing to disease susceptibility and immune regulation in rheumatic diseases. The aim of this review is to discuss how the balance between autophagy and apoptosis may be dysregulated in multiple rheumatic diseases and to dissect the role of autophagy in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. Furthermore, to discuss the potential capacity of currently used disease-modifying antirheumatic drugs (DMARDs) to target and modulate autophagic processes. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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17 pages, 1307 KiB

Open AccessFeature PaperReview

Role of ERLINs in the Control of Cell Fate through Lipid Rafts

by Valeria Manganelli, Agostina Longo, Vincenzo Mattei, Serena Recalchi, Gloria Riitano, Daniela Caissutti, Antonella Capozzi, Maurizio Sorice, Roberta Misasi and Tina Garofalo

Cells 2021, 10(9), 2408; https://doi.org/10.3390/cells10092408 - 13 Sep 2021

Cited by 21 | Viewed by 4668

Abstract

ER lipid raft-associated protein 1 (ERLIN1) and 2 (ERLIN2) are 40 kDa transmembrane glycoproteins belonging to the family of prohibitins, containing a PHB domain. They are generally localized in the endoplasmic reticulum (ER), where ERLIN1 forms a heteroligomeric complex with its closely related [...] Read more.

ER lipid raft-associated protein 1 (ERLIN1) and 2 (ERLIN2) are 40 kDa transmembrane glycoproteins belonging to the family of prohibitins, containing a PHB domain. They are generally localized in the endoplasmic reticulum (ER), where ERLIN1 forms a heteroligomeric complex with its closely related ERLIN2. Well-defined functions of ERLINS are promotion of ER-associated protein degradation, mediation of inositol 1,4,5-trisphosphate (IP₃) receptors, processing and regulation of lipid metabolism. Until now, ERLINs have been exclusively considered protein markers of ER lipid raft-like microdomains. However, under pathophysiological conditions, they have been described within mitochondria-associated endoplasmic reticulum membranes (MAMs), tethering sites between ER and mitochondria, characterized by the presence of specialized raft-like subdomains enriched in cholesterol and gangliosides, which play a key role in the membrane scrambling and function. In this context, it is emerging that ER lipid raft-like microdomains proteins, i.e., ERLINs, may drive mitochondria-ER crosstalk under both physiological and pathological conditions by association with MAMs, regulating the two main processes underlined, survival and death. In this review, we describe the role of ERLINs in determining cell fate by controlling the “interchange” between apoptosis and autophagy pathways, considering that their alteration has a significant impact on the pathogenesis of several human diseases. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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20 pages, 840 KiB

Open AccessFeature PaperReview

Calcium Signaling Regulates Autophagy and Apoptosis

by Pramod Sukumaran, Viviane Nascimento Da Conceicao, Yuyang Sun, Naseem Ahamad, Luis R Saraiva, Senthil Selvaraj and Brij B Singh

Cells 2021, 10(8), 2125; https://doi.org/10.3390/cells10082125 - 18 Aug 2021

Cited by 113 | Viewed by 12601

Abstract

Calcium (Ca²⁺) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca²⁺ channels and Ca²⁺ storage in [...] Read more.

Calcium (Ca²⁺) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca²⁺ channels and Ca²⁺ storage in various organelles is critical in maintaining cytosolic Ca²⁺ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca²⁺ homeostasis is a store operated Ca²⁺ entry (SOCE) mechanism that is activated by the depletion of Ca²⁺ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells. Ca²⁺ has been shown to regulate opposing functions such as autophagy, that promote cell survival; on the other hand, Ca²⁺ also regulates programmed cell death processes such as apoptosis. The functional significance of the TRP/Orai channels has been elaborately studied; however, information on how they can modulate opposing functions and modulate function in excitable and non-excitable cells is limited. Importantly, perturbations in SOCE have been implicated in a spectrum of pathological neurodegenerative conditions. The critical role of autophagy machinery in the pathogenesis of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, would presumably unveil avenues for plausible therapeutic interventions for these diseases. We thus review the role of SOCE-regulated Ca²⁺ signaling in modulating these diverse functions in stem cell, immune regulation and neuromodulation. Full article

(This article belongs to the Special Issue Crosstalk of Autophagy and Apoptosis)

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