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.

Structural Glycobiology and Human Health

2010 ◽  
Vol 38 (5) ◽  
pp. 1329-1332 ◽  
Author(s):  
Barbara Mulloy ◽  
Anthony P. Corfield
Keyword(s):  
Protein Structure ◽  
Human Health ◽  
Protein Interactions ◽  
Viral Infections ◽  
Three Dimensional ◽  
Therapeutic Strategies ◽  
Diverse Group ◽  
Physiological Processes ◽  
Inflammatory Processes ◽  
Health And Disease

The glycans (carbonhydrates) form a diverse group of biomolecules which play active parts in most physiological processes. The field of structural glycobiology concerns the structures of the glycans themselves, the proteins which interact with them and the nature of the interactions between the two. The resulting information is important for our understainding of human health and disease, and for development of new therapeutic strategies. A series of articles is introduced based on the topics covered at the Structural Glycobiology and Human Health Biochemical Society Focused Meeting. Their subjects range from in-depth determinations of three-dimensional protein structure to broad screening techniques for glycan–protein interactions relevant to disease processes, including bacterial, parasitic and viral infections, inflammatory processes, cancer and diabetes.

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 Plant-Derived Extracellular Vesicles: Current Findings,Challenges, and Future Applications

Membranes ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 411
Author(s):  
Nader Kameli ◽  
Anya Dragojlovic-Kerkache ◽  
Paul Savelkoul ◽  
Frank R. Stassen
Keyword(s):  
Human Health ◽  
Extracellular Vesicles ◽  
Preliminary Results ◽  
In Vivo Experiments ◽  
Health And Disease ◽  
Conducting Research ◽  
Protocol Standardization ◽  
Insight Into

In recent years, plant-derived extracellular vesicles (PDEVs) have gained the interest of many experts in fields such as microbiology and immunology, and research in this field has exponentially increased. These nano-sized particles have provided researchers with a number of interesting findings, making their application in human health and disease very promising. Both in vitro and in vivo experiments have shown that PDEVs can exhibit a multitude of effects, suggesting that these vesicles may have many potential future applications, including therapeutics and nano-delivery of compounds. While the preliminary results are promising, there are still some challenges to face, such as a lack of protocol standardization, as well as knowledge gaps that need to be filled. This review aims to discuss various aspects of PDEV knowledge, including their preliminary findings, challenges, and future uses, giving insight into the complexity of conducting research in this field.

scholarly journals Role of Insulin in Health and Disease: An Update

2021 ◽  
Vol 22 (12) ◽  
pp. 6403
Author(s):  
Md Saidur Rahman ◽  
Khandkar Shaharina Hossain ◽  
Sharnali Das ◽  
Sushmita Kundu ◽  
Elikanah Olusayo Adegoke ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Basic Research ◽  
Future Research ◽  
Protective Effects ◽  
Glucose Levels ◽  
Physiological Processes ◽  
Blood Glucose Levels ◽  
Wide Range ◽  
Health And Disease

Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.

scholarly journals SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways

2012 ◽  
Vol 197 (2) ◽  
pp. 219-230 ◽  
Author(s):  
Florian Steinberg ◽  
Kate J. Heesom ◽  
Mark D. Bass ◽  
Peter J. Cullen
Keyword(s):  
Isotope Labeling ◽  
Degradation Pathway ◽  
Lysosomal Degradation ◽  
Sorting Nexins ◽  
Retromer Complex ◽  
Proteomic Approach ◽  
Cytoplasmic Tails ◽  
Npxy Motif ◽  
Global Identification ◽  
Insight Into

The FERM-like domain–containing sorting nexins of the SNX17/SNX27/SNX31 family have been proposed to mediate retrieval of transmembrane proteins from the lysosomal pathway. In this paper, we describe a stable isotope labeling with amino acids in culture–based quantitative proteomic approach that allows an unbiased, global identification of transmembrane cargoes that are rescued from lysosomal degradation by SNX17. This screen revealed that several integrins required SNX17 for their stability, as depletion of SNX17 led to a loss of β1 and β5 integrins and associated a subunits from HeLa cells as a result of increased lysosomal degradation. SNX17 bound to the membrane distal NPXY motif in β integrin cytoplasmic tails, thereby preventing lysosomal degradation of β integrins and their associated a subunits. Furthermore, SNX17-dependent retrieval of integrins did not depend on the retromer complex. Consistent with an effect on integrin recycling, depletion of SNX17 also caused alterations in cell migration. Our data provide mechanistic insight into the retrieval of internalized integrins from the lysosomal degradation pathway, a prerequisite for subsequent recycling of these matrix receptors.

scholarly journals Disruption of inositol biosynthesis through targeted mutagenesis in Dictyostelium discoideum: generation and characterization of inositol-auxotrophic mutants

2006 ◽  
Vol 397 (3) ◽  
pp. 509-518 ◽  
Author(s):  
Andreas Fischbach ◽  
Stephan Adelt ◽  
Alexander Müller ◽  
Günter Vogel
Keyword(s):  
Dictyostelium Discoideum ◽  
Genetic Manipulation ◽  
Inositol Phosphate ◽  
Targeted Mutagenesis ◽  
Inositol Polyphosphate ◽  
Fluid Medium ◽  
Physiological Processes ◽  
Evolutionarily Conserved ◽  
Cellular Slime

myo-Inositol and its downstream metabolites participate in diverse physiological processes. Nevertheless, considering their variety, it is likely that additional roles are yet to be uncovered. Biosynthesis of myo-inositol takes place via an evolutionarily conserved metabolic pathway and is strictly dependent on inositol-3-phosphate synthase (EC 5.5.1.4). Genetic manipulation of this enzyme will disrupt the cellular inositol supply. Two methods, based on gene deletion and antisense strategy, were used to generate mutants of the cellular slime mould Dictyostelium discoideum. These mutants are inositol-auxotrophic and show phenotypic changes under inositol starvation. One remarkable attribute is their inability to live by phagocytosis of bacteria, which is the exclusive nutrient source in their natural environment. Cultivated on fluid medium, the mutants lose their viability when deprived of inositol for longer than 24 h. Here, we report a study of the alterations in the first 24 h in cellular inositol, inositol phosphate and phosphoinositide concentrations, whereby a rapidly accumulating phosphorylated compound was detected. After its identification as 2,3-BPG (2,3-bisphosphoglycerate), evidence could be found that the internal disturbances of inositol homoeostasis trigger the accumulation. In a first attempt to characterize this as a physiologically relevant response, the efficient in vitro inhibition of a D. discoideum inositol-polyphosphate 5-phosphatase (EC 3.1.3.56) by 2,3-BPG is presented.

scholarly journals Early Developmental Conditioning of Later Health and Disease: Physiology or Pathophysiology?

2014 ◽  
Vol 94 (4) ◽  
pp. 1027-1076 ◽  
Author(s):  
M. A. Hanson ◽  
P. D. Gluckman
Keyword(s):  
Animal Studies ◽  
Developmental Plasticity ◽  
Current Knowledge ◽  
Evolutionary Developmental Biology ◽  
Noncommunicable Disease ◽  
Normal Range ◽  
Physiological Processes ◽  
New Concepts ◽  
Health And Disease ◽  
Underlying Mechanisms

Extensive experimental animal studies and epidemiological observations have shown that environmental influences during early development affect the risk of later pathophysiological processes associated with chronic, especially noncommunicable, disease (NCD). This field is recognized as the developmental origins of health and disease (DOHaD). We discuss the extent to which DOHaD represents the result of the physiological processes of developmental plasticity, which may have potential adverse consequences in terms of NCD risk later, or whether it is the manifestation of pathophysiological processes acting in early life but only becoming apparent as disease later. We argue that the evidence suggests the former, through the operation of conditioning processes induced across the normal range of developmental environments, and we summarize current knowledge of the physiological processes involved. The adaptive pathway to later risk accords with current concepts in evolutionary developmental biology, especially those concerning parental effects. Outside the normal range, effects on development can result in nonadaptive processes, and we review their underlying mechanisms and consequences. New concepts concerning the underlying epigenetic and other mechanisms involved in both disruptive and nondisruptive pathways to disease are reviewed, including the evidence for transgenerational passage of risk from both maternal and paternal lines. These concepts have wider implications for understanding the causes and possible prevention of NCDs such as type 2 diabetes and cardiovascular disease, for broader social policy and for the increasing attention paid in public health to the lifecourse approach to NCD prevention.

Insight into the practical models for prediciting the essential role of the cytochrome P450-mediated biotransformation in emodin-associated hepatotoxicity

Toxicology ◽  
2021 ◽  
Vol 462 ◽  
pp. 152930
Author(s):  
Tingting Zhang ◽  
Xiaomei He ◽  
Lanlan Sun ◽  
Dong Wang ◽  
Shuya Zhang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Essential Role ◽  
Insight Into

A reactive center loop–based prediction platform to enhance the design of therapeutic SERPINs

2021 ◽  
Vol 118 (45) ◽  
pp. e2108458118
Author(s):  
Wariya Sanrattana ◽  
Thibaud Sefiane ◽  
Simone Smits ◽  
Nadine D. van Kleef ◽  
Marcel H. Fens ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Serine Proteases ◽  
Protein C ◽  
Activated Protein C ◽  
Reactive Center Loop ◽  
Physiological Processes ◽  
Naturally Occurring ◽  
Reactive Center ◽  
Insight Into

Serine proteases are essential for many physiological processes and require tight regulation by serine protease inhibitors (SERPINs). A disturbed SERPIN–protease balance may result in disease. The reactive center loop (RCL) contains an enzymatic cleavage site between the P1 through P1’ residues that controls SERPIN specificity. This RCL can be modified to improve SERPIN function; however, a lack of insight into sequence–function relationships limits SERPIN development. This is complicated by more than 25 billion mutants needed to screen the entire P4 to P4’ region. Here, we developed a platform to predict the effects of RCL mutagenesis by using α1-antitrypsin as a model SERPIN. We generated variants for each of the residues in P4 to P4’ region, mutating them into each of the 20 naturally occurring amino acids. Subsequently, we profiled the reactivity of the resulting 160 variants against seven proteases involved in coagulation. These profiles formed the basis of an in silico prediction platform for SERPIN inhibitory behavior with combined P4 to P4’ RCL mutations, which were validated experimentally. This prediction platform accurately predicted SERPIN behavior against five out of the seven screened proteases, one of which was activated protein C (APC). Using these findings, a next-generation APC-inhibiting α1-antitrypsin variant was designed (KMPR/RIRA; / indicates the cleavage site). This variant attenuates blood loss in an in vivo hemophilia A model at a lower dosage than the previously developed variant AIKR/KIPP because of improved potency and specificity. We propose that this SERPIN-based RCL mutagenesis approach improves our understanding of SERPIN behavior and will facilitate the design of therapeutic SERPINs.

scholarly journals Therapeutic Depletion of Axotomy Competent Cells in Amyotrophic Lateral Sclerosis (ALS)

2019 ◽  
Vol 2 (1) ◽  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Networks ◽  
Large Protein ◽  
Anatomical Structures ◽  
Therapy Options ◽  
New Therapy ◽  
Competent Cells ◽  
Health And Disease ◽  
Insight Into ◽  
Lateral Sclerosis

The present paper addresses anatomically resolved protein networks by using the Imaging Cycler Microscopy (ICM/TIS) [1,2]. ICM is capable of resolving protein networks in intact anatomical structures at a power of combinatorial molecular resolution of 65,553k , where k is the number of co-mapped proteins, e.g. 100 proteins [1-4]. This method provides insight into the laws of the spatial communication of large protein networks in health and disease, which is essential for new therapy options in diseases.

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