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Molecular Research of Autophagy and Apoptosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Role of Xenobiotics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 49486

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Prof. Dr. Krisztina Takács-Vellai

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Department of Biological Anthropology, Institute of Biology, Eötvös Loránd University, Budapest, Hungary
Interests: cell death; cell survival; autophagy; apoptosis; phagocytosis; inflammation; model organisms; lysosome; tumor metabolism; therapy resistance
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Dear Colleagues,

Balance between cell death and survival is of key importance in maintaining cellular homeostasis. Three major types of programmed cell death (PCD) have been distinguished: apoptosis (type I), autophagic cell death (type II), and necrosis (type III), which are interconnected through molecular crosstalk mechanisms. In addition to human studies, research on model organisms contributed significantly to identification of conserved molecular pathways constituting different types of PCD. Characterization of the complex interplay among PCD processes is crucial as it underlies the pathogenesis of multiple diseases, especially cancer.

Recent studies show that apoptosis is a barrier that tumor cells have to overcome in order to survive. Elimination of apoptotic cell debris by phagocytosis is required to prevent inflammation, which is known as a factor that might favour tumor progression. Autophagy, which was originally characterized as a cell survival mechanism in response to starvation but also known as a cell death modulator, may influence the pathological conditions of cancer by altering metabolic conditions.

Further elucidation of basic molecular mechanisms playing a role in PCD processes, furthermore better understanding of their interactions may pave the way for new treatment strategies of cancer.

Prof. Dr. Krisztina Takács-Vellai
Guest Editor

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Keywords

cell death
cell survival
autophagy
apoptosis
phagocytosis
inflammation
model organisms
lysosome
tumor metabolism
therapy resistance

Related Special Issue

Molecular Research of Autophagy and Apoptosis 2022 in International Journal of Molecular Sciences (1 article)

Published Papers (11 papers)

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Editorial

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4 pages, 533 KiB

Open AccessEditorial

Apoptosis and Autophagy, Different Modes of Cell Death: How to Utilize Them to Fight Diseases?

by Krisztina Takács-Vellai

Int. J. Mol. Sci. 2023, 24(14), 11609; https://doi.org/10.3390/ijms241411609 - 18 Jul 2023

Cited by 1 | Viewed by 734

Abstract

A careful balance between cell death and survival is of key importance when it comes to the maintenance of cellular homeostasis [...] Full article

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

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Research

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20 pages, 4604 KiB

Open AccessArticle

Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells

by Titanilla Dankó, Gábor Petővári, Dániel Sztankovics, Dorottya Moldvai, Regina Raffay, Péter Lőrincz, Tamás Visnovitz, Viktória Zsiros, Gábor Barna, Ágnes Márk, Ildikó Krencz and Anna Sebestyén

Int. J. Mol. Sci. 2021, 22(15), 8019; https://doi.org/10.3390/ijms22158019 - 27 Jul 2021

Cited by 16 | Viewed by 3297

Abstract

Metabolic alteration is characteristic during tumour growth and therapy; however, targeting metabolic rewiring could overcome therapy resistance. mTOR hyperactivity, autophagy and other metabolic processes, including mitochondrial functions, could be targeted in breast cancer progression. We investigated the growth inhibitory mechanism of rapamycin + doxycycline treatment in human breast cancer model systems. Cell cycle and cell viability, including apoptotic and necrotic cell death, were analysed using flow cytometry, caspase activity measurements and caspase-3 immunostainings. mTOR-, autophagy-, necroptosis-related proteins and treatment-induced morphological alterations were analysed by Wes^TM, Western blot, immunostainings and transmission electron microscopy. The rapamycin + doxycycline combination decreased tumour proliferation in about 2/3rd of the investigated cell lines. The continuous treatment reduced tumour growth significantly both in vivo and in vitro. The effect after short-term treatment was reversible; however, autophagic vacuoles and degrading mitochondria were detected simultaneously, and the presence of mitophagy was also observed after the long-term rapamycin + doxycycline combination treatment. The rapamycin + doxycycline combination did not cause apoptosis or necrosis/necroptosis, but the alterations in autophagy- and mitochondria-related protein levels (LC3-B-II/I, p62, MitoTracker, TOM20 and certain co-stainings) were correlated to autophagy induction and mitophagy, without mitochondria repopulation. Based on these results, we suggest considering inducing metabolic stress and targeting mTOR hyperactivity and mitochondrial functions in combined anti-cancer treatments. Full article

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

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10 pages, 20858 KiB

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6-Azauridine Induces Autophagy-Mediated Cell Death via a p53- and AMPK-Dependent Pathway

by Yeo-Eun Cha, Rackhyun Park, Minsu Jang, Yea-In Park, Ayane Yamamoto, Won Keun Oh, Eun-Ju Lee and Junsoo Park

Int. J. Mol. Sci. 2021, 22(6), 2947; https://doi.org/10.3390/ijms22062947 - 14 Mar 2021

Cited by 9 | Viewed by 2515

Abstract

6-Azauridine (6-AZA), a pyrimidine nucleoside analogue, is known to exhibit both antitumor and antiviral activities. Although 6-AZA was discovered more than 60 years ago, the cellular effects of this compound are yet to be elucidated. Here, we report that 6-AZA regulates autophagy-mediated cell death in various human cancer cells, where 6-AZA treatment activates autophagic flux through the activation of lysosomal function. Furthermore, 6-AZA exhibited cytotoxicity in all cancer cells studied, although the mechanisms of action were diverse. In H460 cells, 6-AZA treatment induced apoptosis, and the extent of the latter could be reduced by treatment with chloroquine (CQ), a lysosomal inhibitor. However, 6-AZA treatment resulted in cell cycle arrest in H1299 cells, which could not be reversed by CQ. The cytotoxicity associated with 6-AZA treatment could be linearly correlated to the degree of autophagy-mediated cell death. In addition, we demonstrated that the cytotoxic effect of 6-AZA was dependent on AMPK and p53. These results collectively indicate that autophagy-mediated cell death triggered by 6-AZA contributes to its antitumor effect. Full article

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

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Review

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15 pages, 2582 KiB

Open AccessReview

Mitochondrial Lipids: From Membrane Organization to Apoptotic Facilitation

by Aikaterini Poulaki and Stavroula Giannouli

Int. J. Mol. Sci. 2022, 23(7), 3738; https://doi.org/10.3390/ijms23073738 - 29 Mar 2022

Cited by 11 | Viewed by 3794

Abstract

Mitochondria are the most complex intracellular organelles, their function combining energy production for survival and apoptosis facilitation for death. Such a multivariate physiology is structurally and functionally reflected upon their membrane configuration and lipid composition. Mitochondrial double membrane lipids, with cardiolipin as the protagonist, show an impressive level of complexity that is mandatory for maintenance of mitochondrial health and protection from apoptosis. Given that lipidomics is an emerging field in cancer research and that mitochondria are the organelles with the most important role in malignant maintenance knowledge of the mitochondrial membrane, lipid physiology in health is mandatory. In this review, we will thus describe the delicate nature of the healthy mitochondrial double membrane and its role in apoptosis. Emphasis will be given on mitochondrial membrane lipids and the changes that they undergo during apoptosis induction and progression. Full article

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

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15 pages, 1944 KiB

Open AccessReview

The Role of Autophagy and Apoptosis in Neuropathic Pain Formation

by Ming-Feng Liao, Kwok-Tung Lu, Jung-Lung Hsu, Chih-Hong Lee, Mei-Yun Cheng and Long-Sun Ro

Int. J. Mol. Sci. 2022, 23(5), 2685; https://doi.org/10.3390/ijms23052685 - 28 Feb 2022

Cited by 25 | Viewed by 3846

Abstract

Neuropathic pain indicates pain caused by damage to the somatosensory system and is difficult to manage and treat. A new treatment strategy urgently needs to be developed. Both autophagy and apoptosis are critical adaptive mechanisms when neurons encounter stress or damage. Recent studies have shown that, after nerve damage, both autophagic and apoptotic activities in the injured nerve, dorsal root ganglia, and spinal dorsal horn change over time. Many studies have shown that upregulated autophagic activities may help myelin clearance, promote nerve regeneration, and attenuate pain behavior. On the other hand, there is no direct evidence that the inhibition of apoptotic activities in the injured neurons can attenuate pain behavior. Most studies have only shown that agents can simultaneously attenuate pain behavior and inhibit apoptotic activities in the injured dorsal root ganglia. Autophagy and apoptosis can crosstalk with each other through various proteins and proinflammatory cytokine expressions. Proinflammatory cytokines can promote both autophagic/apoptotic activities and neuropathic pain formation, whereas autophagy can inhibit proinflammatory cytokine activities and further attenuate pain behaviors. Thus, agents that can enhance autophagic activities but suppress apoptotic activities on the injured nerve and dorsal root ganglia can treat neuropathic pain. Here, we summarized the evolving changes in apoptotic and autophagic activities in the injured nerve, dorsal root ganglia, spinal cord, and brain after nerve damage. This review may help in further understanding the treatment strategy for neuropathic pain during nerve injury by modulating apoptotic/autophagic activities and proinflammatory cytokines in the nervous system. Full article

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

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13 pages, 1427 KiB

Open AccessReview

Regulation of Autophagy by the Glycogen Synthase Kinase-3 (GSK-3) Signaling Pathway

by Hsuan-Yeh Pan and Mallika Valapala

Int. J. Mol. Sci. 2022, 23(3), 1709; https://doi.org/10.3390/ijms23031709 - 01 Feb 2022

Cited by 16 | Viewed by 4316

Abstract

Autophagy is a vital cellular mechanism that benefits cellular maintenance and survival during cell stress. It can eliminate damaged or long-lived organelles and improperly folded proteins to maintain cellular homeostasis, development, and differentiation. Impaired autophagy is associated with several diseases such as cancer, neurodegenerative diseases, and age-related macular degeneration (AMD). Several signaling pathways are associated with the regulation of the autophagy pathway. The glycogen synthase kinase-3 signaling pathway was reported to regulate the autophagy pathway. In this review, we will discuss the mechanisms by which the GSK-3 signaling pathway regulates autophagy. Autophagy and lysosomal function are regulated by transcription factor EB (TFEB). GSK-3 was shown to be involved in the regulation of TFEB nuclear expression in an mTORC1-dependent manner. In addition to mTORC1, GSK-3β also regulates TFEB via the protein kinase C (PKC) and the eukaryotic translation initiation factor 4A-3 (eIF4A3) signaling pathways. In addition to TFEB, we will also discuss the mechanisms by which the GSK-3 signaling pathway regulates autophagy by modulating other signaling molecules and autophagy inducers including, mTORC1, AKT and ULK1. In summary, this review provides a comprehensive understanding of the role of the GSK-3 signaling pathway in the regulation of autophagy. Full article

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

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42 pages, 7255 KiB

Open AccessReview

Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy

by Mahmoud Izadi, Tayyiba Akbar Ali and Ehsan Pourkarimi

Int. J. Mol. Sci. 2021, 22(22), 12466; https://doi.org/10.3390/ijms222212466 - 18 Nov 2021

Cited by 15 | Viewed by 4826

Abstract

Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings. Full article

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

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17 pages, 774 KiB

Open AccessReview

Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model

by Anam Naseer, Snober Shabnam Mir, Krisztina Takacs-Vellai and Aamir Nazir

Int. J. Mol. Sci. 2021, 22(22), 12263; https://doi.org/10.3390/ijms222212263 - 12 Nov 2021

Cited by 3 | Viewed by 3161

Abstract

Age-associated neurodegenerative diseases are known to have “impaired protein clearance” as one of the key features causing their onset and progression. Hence, homeostasis is the key to maintaining balance throughout the cellular system as an organism ages. Any imbalance in the protein clearance machinery is responsible for accumulation of unwanted proteins, leading to pathological consequences—manifesting in neurodegeneration and associated debilitating outcomes. Multiple processes are involved in regulating this phenomenon; however, failure to regulate the autophagic machinery is a critical process that hampers the protein clearing pathway, leading to neurodegeneration. Another important and widely known component that plays a role in modulating neurodegeneration is a class of proteins called sirtuins. These are class III histone deacetylases (HDACs) that are known to regulate various vital processes such as longevity, genomic stability, transcription and DNA repair. These enzymes are also known to modulate neurodegeneration in an autophagy-dependent manner. Considering its genetic relevance and ease of studying disease-related endpoints in neurodegeneration, the model system Caenorhabditis elegans has been successfully employed in deciphering various functional outcomes related to critical protein molecules, cell death pathways and their association with ageing. This review summarizes the vital role of sirtuins and autophagy in ageing and neurodegeneration, in particular highlighting the knowledge obtained using the C. elegans model system. Full article

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

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26 pages, 1932 KiB

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Conserved and Distinct Elements of Phagocytosis in Human and C. elegans

by Szilvia Lukácsi, Zsolt Farkas, Éva Saskői, Zsuzsa Bajtay and Krisztina Takács-Vellai

Int. J. Mol. Sci. 2021, 22(16), 8934; https://doi.org/10.3390/ijms22168934 - 19 Aug 2021

Cited by 7 | Viewed by 2873

Abstract

Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis—the engulfment and elimination of dying cells and cell debris—are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance. Full article

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

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19 pages, 2131 KiB

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Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging

by Jean-Philippe Leduc-Gaudet, Sabah N. A. Hussain, Esther Barreiro and Gilles Gouspillou

Int. J. Mol. Sci. 2021, 22(15), 8179; https://doi.org/10.3390/ijms22158179 - 30 Jul 2021

Cited by 95 | Viewed by 14452

Abstract

The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca²⁺ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy—the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly. Full article

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

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28 pages, 3848 KiB

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Two Faces of Autophagy in the Struggle against Cancer

by Anna Chmurska, Karolina Matczak and Agnieszka Marczak

Int. J. Mol. Sci. 2021, 22(6), 2981; https://doi.org/10.3390/ijms22062981 - 15 Mar 2021

Cited by 32 | Viewed by 3841

Abstract

Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called “autophagy paradox”, and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell’s energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a “double-edged sword”. This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes. Full article

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

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