scholarly journals Inflammasome and Mitophagy Connection in Health and Disease

2020 ◽  
Vol 21 (13) ◽  
pp. 4714 ◽  
Author(s):  
Jae-Min Yuk ◽  
Prashanta Silwal ◽  
Eun-Kyeong Jo
Keyword(s):  
Cell Death ◽  
Small Molecules ◽  
Essential Role ◽  
Inflammatory Diseases ◽  
Novel Therapies ◽  
Compelling Evidence ◽  
Biological Functions ◽  
Intracellular Protein ◽  
Mitochondrial Homeostasis ◽  
Health And Disease

The inflammasome is a large intracellular protein complex that activates inflammatory caspase-1 and induces the maturation of interleukin (IL)-1β and IL-18. Mitophagy plays an essential role in the maintenance of mitochondrial homeostasis during stress. Previous studies have indicated compelling evidence of the crosstalk between inflammasome and mitophagy. Mitophagy regulation of the inflammasome, or vice versa, is crucial for various biological functions, such as controlling inflammation and metabolism, immune and anti-tumor responses, and pyroptotic cell death. Uncontrolled regulation of the inflammasome often results in pathological inflammation and pyroptosis, and causes a variety of human diseases, including metabolic and inflammatory diseases, infection, and cancer. Here, we discuss how improved understanding of the interactions between inflammasome and mitophagy can lead to novel therapies against various disease pathologies, and how the inflammasome-mitophagy connection is currently being targeted pharmacologically by diverse agents and small molecules. A deeper understanding of the inflammasome-mitophagy connection will provide new insights into human health and disease through the balance between mitochondrial clearance and pathology.

scholarly journals Mitochondrial Iron in Human Health and Disease

2019 ◽  
Vol 81 (1) ◽  
pp. 453-482 ◽  
Author(s):  
Diane M. Ward ◽  
Suzanne M. Cloonan
Keyword(s):  
Human Health ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Biological Functions ◽  
Mitochondrial Homeostasis ◽  
Innate Immune Signaling ◽  
Mitochondrial Iron ◽  
Health And Disease

Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease.

scholarly journals Are metacaspases caspases?

2007 ◽  
Vol 179 (3) ◽  
pp. 375-380 ◽  
Author(s):  
Dominique Vercammen ◽  
Wim Declercq ◽  
Peter Vandenabeele ◽  
Frank Van Breusegem
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Caspase Activity ◽  
Compelling Evidence ◽  
Biological Functions ◽  
Fungal Cell ◽  
Cysteine Peptidases

The identification of caspases as major regulators of apoptotic cell death in animals initiated a quest for homologous peptidases in other kingdoms. With the discovery of metacaspases in plants, fungi, and protozoa, this search had apparently reached its goal. However, there is compelling evidence that metacaspases lack caspase activity and that they are not responsible for the caspaselike activities detected during plant and fungal cell death. In this paper, we attempt to broaden the discussion of these peptidases to biological functions beyond apoptosis and cell death. We further suggest that metacaspases and paracaspases, although sharing structural and mechanistic features with the metazoan caspases, form a distinct family of clan CD cysteine peptidases.

scholarly journals SIRT3 Is a Stress-Responsive Deacetylase in Cardiomyocytes That Protects Cells from Stress-Mediated Cell Death by Deacetylation of Ku70

2008 ◽  
Vol 28 (20) ◽  
pp. 6384-6401 ◽  
Author(s):  
Nagalingam R. Sundaresan ◽  
Sadhana A. Samant ◽  
Vinodkumar B. Pillai ◽  
Senthilkumar B. Rajamohan ◽  
Mahesh P. Gupta
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Gene Regulation ◽  
Essential Role ◽  
Short Form ◽  
Biological Functions ◽  
Proapoptotic Protein ◽  
Long Form ◽  
And Oxidative Stress

ABSTRACT There are seven SIRT isoforms in mammals, with diverse biological functions including gene regulation, metabolism, and apoptosis. Among them, SIRT3 is the only sirtuin whose increased expression has been shown to correlate with an extended life span in humans. In this study, we examined the role of SIRT3 in murine cardiomyocytes. We found that SIRT3 is a stress-responsive deacetylase and that its increased expression protects myocytes from genotoxic and oxidative stress-mediated cell death. We show that, like human SIRT3, mouse SIRT3 is expressed in two forms, a ∼44-kDa long form and a ∼28-kDa short form. Whereas the long form is localized in the mitochondria, nucleus, and cytoplasm, the short form is localized exclusively in the mitochondria of cardiomyocytes. During stress, SIRT3 levels are increased not only in mitochondria but also in the nuclei of cardiomyocytes. We also identified Ku70 as a new target of SIRT3. SIRT3 physically binds to Ku70 and deacetylates it, and this promotes interaction of Ku70 with the proapoptotic protein Bax. Thus, under stress conditions, increased expression of SIRT3 protects cardiomyocytes, in part by hindering the translocation of Bax to mitochondria. These studies underscore an essential role of SIRT3 in the survival of cardiomyocytes in stress situations.

scholarly journals The Role of Mitophagy in Regulating Cell Death

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Sunao Li ◽  
Jiaxin Zhang ◽  
Chao Liu ◽  
Qianliang Wang ◽  
Jun Yan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytosolic Calcium ◽  
Cellular Functions ◽  
Power Generators ◽  
Unfolded Protein ◽  
Mitochondrial Homeostasis ◽  
Cell Death Pathways ◽  
Health And Disease ◽  
Protein Response

Mitochondria are multifaceted organelles that serve to power critical cellular functions, including act as power generators of the cell, buffer cytosolic calcium overload, production of reactive oxygen species, and modulating cell survival. The structure and the cellular location of mitochondria are critical for their function and depend on highly regulated activities such as mitochondrial quality control (MQC) mechanisms. The MQC is regulated by several sets of processes: mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy, and other mitochondrial proteostasis mechanisms such as mitochondrial unfolded protein response (mtUPR) or mitochondrial-derived vesicles (MDVs). These processes are important for the maintenance of mitochondrial homeostasis, and alterations in the mitochondrial function and signaling are known to contribute to the dysregulation of cell death pathways. Recent studies have uncovered regulatory mechanisms that control the activity of the key components for mitophagy. In this review, we discuss how mitophagy is controlled and how mitophagy impinges on health and disease through regulating cell death.

scholarly journals E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

2021 ◽  
Author(s):  
Yuhua Shi ◽  
Yang Yang ◽  
Weilv Xu ◽  
Wei Xu ◽  
Xinyu Fu ◽  
...  
Keyword(s):  
Cell Death ◽  
Ubiquitin Ligase ◽  
Essential Role ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
E3 Ubiquitin Ligase ◽  
Positive Regulator ◽  
Ldh Release

Gasdermin D (GSDMD) participates in activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

scholarly journals Functional Lipids in Autoimmune Inflammatory Diseases

2020 ◽  
Vol 21 (9) ◽  
pp. 3074
Author(s):  
Michele Dei Cas ◽  
Gabriella Roda ◽  
Feng Li ◽  
Francesco Secundo
Keyword(s):  
Immune Responses ◽  
Small Molecules ◽  
Lupus Erythematosus ◽  
Inflammatory Process ◽  
Recent Literature ◽  
Inflammatory Diseases ◽  
Biological Functions ◽  
Bioactive Lipids ◽  
Inflammatory Processes

Lipids are apolar small molecules known not only as components of cell membranes but also, in recent literature, as modulators of different biological functions. Herein, we focused on the bioactive lipids that can influence the immune responses and inflammatory processes regulating vascular hyperreactivity, pain, leukocyte trafficking, and clearance. In the case of excessive pro-inflammatory lipid activity, these lipids also contribute to the transition from acute to chronic inflammation. Based on their biochemical function, these lipids can be divided into different families, including eicosanoids, specialized pro-resolving mediators, lysoglycerophospholipids, sphingolipids, and endocannabinoids. These bioactive lipids are involved in all phases of the inflammatory process and the pathophysiology of different chronic autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type-1 diabetes, and systemic lupus erythematosus.

scholarly journals Neuronal Mitophagy: Friend or Foe?

2021 ◽  
Vol 8 ◽  
Author(s):  
Christina Doxaki ◽  
Konstantinos Palikaras
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitochondrial Content ◽  
Mitochondrial Homeostasis ◽  
Neuronal Homeostasis ◽  
Age Related ◽  
Health And Disease ◽  
Mitochondrial Number

Maintenance of neuronal homeostasis is a challenging task, due to unique cellular organization and bioenergetic demands of post-mitotic neurons. It is increasingly appreciated that impairment of mitochondrial homeostasis represents an early sign of neuronal dysfunction that is common in both age-related neurodegenerative as well as in neurodevelopmental disorders. Mitochondrial selective autophagy, known as mitophagy, regulates mitochondrial number ensuring cellular adaptation in response to several intracellular and environmental stimuli. Mounting evidence underlines that deregulation of mitophagy levels has an instructive role in the process of neurodegeneration. Although mitophagy induction mediates the elimination of damaged mitochondria and confers neuroprotection, uncontrolled runaway mitophagy could reduce mitochondrial content overstressing the remaining organelles and eventually triggering neuronal cell death. Unveiling the molecular mechanisms of neuronal mitophagy and its intricate role in neuronal survival and cell death, will assist in the development of novel mitophagy modulators to promote cellular and organismal homeostasis in health and disease.

scholarly journals Mitophagy pathways in health and disease

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Samuel A. Killackey ◽  
Dana J. Philpott ◽  
Stephen E. Girardin
Keyword(s):  
Essential Role ◽  
Complex Nature ◽  
Diverse Group ◽  
Mitochondrial Network ◽  
Lysosomal Degradation ◽  
Mitochondrial Homeostasis ◽  
Physiological Processes ◽  
Evolutionarily Conserved ◽  
Health And Disease ◽  
Insight Into

Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into the complex nature of the overlapping pathways regulating mitophagy illustrate mitophagy’s essential role in maintaining the health of the mitochondrial network. In this review, we highlight recent studies that have changed the way mitophagy is understood, from initiation through lysosomal degradation. We outline the numerous mitophagic receptors and triggers, with a focus on basal and physiologically relevant cues, offering insight into why they lead to mitochondrial removal. We also explore how mitophagy maintains mitochondrial homeostasis at the organ and system levels and how a loss of mitophagy may play a role in a diverse group of diseases, including cardiovascular, metabolic, and neurodegenerative diseases. With disrupted mitophagy affecting such a wide array of physiological processes, a deeper understanding of how to modulate mitophagy could provide avenues for numerous therapies.

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