Search Results (592)

The regulation of calcium (Ca²⁺) homeostasis is a critical process in both plant and animal systems, involving complex interplay between various organelles and a diverse network of channels, pumps, and transporters. This review provides a concise overview of inter-organellar Ca²⁺ homeostasis, highlighting key regulators and mechanisms in plant and animal cells. We discuss the roles of key Ca²⁺ channels and transporters, including IP₃Rs, RyRs, TPCs, MCUs, TRPMLs, and P2XRs in animals, as well as their plant counterparts. Here, we explore recent innovations in structural biology and advanced microscopic techniques that have enhanced our understanding of these proteins’ structure, functions, and regulations. We examine the importance of membrane contact sites in facilitating Ca²⁺ transfer between organelles and the specific expression patterns of Ca²⁺ channels and transporters. Furthermore, we address the physiological implications of inter-organellar Ca²⁺ homeostasis and its relevance in various pathological conditions. For extended comparability, a brief excursus into bacterial intracellular Ca²⁺ homeostasis is also made. This meta-analysis aims to bridge the gap between plant and animal Ca²⁺ signaling research, identifying common themes and unique adaptations in these diverse biological systems. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

Chloroplasts, as the organelles primarily responsible for photosynthesis, require a substantial supply of iron ions. Conversely, due to Fe toxicity, the homeostasis of these ions is subject to tight regulation. Permease in chloroplast 1 (PIC1) has been identified as the primary iron importer into chloroplasts. However, previous studies suggested the existence of a distinct pathway for Fe transfer to chloroplasts, likely involving mitoferrin-like 1 (MFL1) protein. In this work, Arabidopsis MFL1 (AtMFL1) and its cucumber homolog (CsMFL1) were characterized using, among others, Arabidopsis protoplasts as well as both yeast and Arabidopsis mutants. Localization of both proteins in chloroplasts has been shown to be mediated via an N-terminal transit peptide. At the gene level, MFL1 expression profiles differed between the model plant and the crop plant under varying Fe availability. The expression of other genes involved in chloroplast Fe homeostasis, including iron acquisition, trafficking, and storage, was affected to some extent in both AtMFL1 knockout and overexpressing plants. Moreover, root growth and photosynthetic parameters changed unfavorably in the mutant lines. The obtained results imply that AtMFL1 and CsMFL1, as putative chloroplast iron transporters, play a role in both iron management and the proper functioning of the plant. Full article

Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) serves as a tethering factor that interacts with various proteins and recruits these proteins to the ER surface, exerting multiple functions, such as organelle membrane tethering, lipid transfer between organelles, regulation of calcium homeostasis, autophagy, and the unfolded protein response (UPR). Its interaction is often mediated by its MSP (major sperm) domain, which binds with FFAT (two phenylalanines in an acidic tract)-motif-containing proteins. However, pathogenic variations, such as P56S, P56H, and T46I, in the VAPB MSP domain lead to the familial form of amyotrophic lateral sclerosis (ALS8). Still, the underlying pathophysiology of ALS8 due to pathogenic variations in the VAPB MSP domain remains elusive. In this study, we conducted molecular dynamics (MD) simulations to understand the pathogenic-variant-derived changes in the structural dynamics of the VAPB MSP domain. We found that pathogenic variants altered the fluctuations and conformational dynamics of the VAPB protein. Analyzing the organizations of the secondary structure revealed that pathogenic variants changed the composition of secondary structure elements, especially increasing the proportion of α-helix while reducing β-sheet formation, which might affect the organelle tethering and other functions of VAPB, as well as VAPB homodimer and heterodimer formation. Taken together, these findings can be further investigated through in vivo and/or in vitro studies to not only clarify the pathophysiology of ALS8 resulting from VAPB MSP domain pathogenic variants but also develop novel therapeutics for the disease that restore the native structural organizations as well as fluctuations and motions. Full article

Autophagy is a highly conserved cellular process that plays a crucial role in maintaining cellular homeostasis by degrading damaged organelles, misfolded proteins, and other cellular components. p62/SQSTM1 functions as a selective autophagy receptor by binding polyubiquitinated cargo through its UBA domain and linking it to microtubule-associated protein light chain 3 (LC3)-decorated autophagosomes. Moreover, p62 acts as a signaling hub and is essential in response to various stressors, including nutrient deprivation and oxidative stress. Post-translational modifications (PTMs) critically regulate p62’s multifaceted roles, controlling p62’s phase separation, cargo recruitment, signaling interactions, and autophagic degradation efficiency. The dysregulation of p62 PTMs is closely related to the occurrence and development of human diseases, particularly neurodegenerative disorders and certain cancers. This review summarizes the main PTM events of p62 discovered to date that influence the autophagy process, including phosphorylation, acetylation, ubiquitination, and S-acylation, as well as their known contributions to protein aggregation and disease. The PTMs of p62 dynamically regulate autophagy, protein aggregation, and cellular signaling, underscoring its importance as a potential therapeutic target and biomarker for these diseases. Full article

Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and organelles. Although the specific mechanisms governing various aspects of selective autophagy have not been fully understood, numerous studies have revealed that the dysregulation of autophagy-related genes significantly influences cellular homeostasis and contributes to a wide range of human diseases, particularly cancers, neurodegenerative disorders and inflammatory diseases. Notably, accumulating evidence highlights the complex, dual role of autophagy in cancer development. Thus, this review systematically summarizes the molecular mechanisms of autophagy and presents the latest research on its involvement in both pro- and anti-tumor progression. Furthermore, we discuss the role of autophagy in cancer development and summarize advancement in tumor therapies targeting autophagy. Full article

Calcium (Ca²⁺) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca²⁺ concentration is tightly regulated by a balance between Ca²⁺ mobilization mechanisms, including Ca²⁺ release from the intracellular stores in the sarcoplasmic/endoplasmic reticulum and Ca²⁺ entry via voltage-dependent, transient-receptor potential, and store-operated Ca²⁺ channels, and Ca²⁺ elimination pathways including Ca²⁺ extrusion by the plasma membrane Ca²⁺-ATPase and Na⁺/Ca²⁺ exchanger and Ca²⁺ re-uptake by the sarco(endo)plasmic reticulum Ca²⁺-ATPase and the mitochondria. Some cell membranes/organelles are multifunctional and have both Ca²⁺ mobilization and Ca²⁺ removal pathways. Also, the individual Ca²⁺ handling pathways could be integrated to function in a regenerative, capacitative, cooperative, bidirectional, or reciprocal feed-forward or feed-back manner. Disruption of these pathways causes dysregulation of the Ca²⁺ signaling dynamics and leads to pathological cardiovascular conditions such as hypertension, coronary artery disease, atherosclerosis, and vascular calcification. In the endothelium, dysregulated Ca²⁺ signaling impairs nitric oxide production, reduces vasodilatory capacity, and increases vascular permeability. In VSMCs, Ca²⁺-dependent phosphorylation of the myosin light chain and Ca²⁺ sensitization by protein kinase-C (PKC) and Rho-kinase (ROCK) increase vascular tone and could lead to increased blood pressure and hypertension. Ca²⁺ activation of matrix metalloproteinases causes collagen/elastin imbalance and promotes vascular remodeling. Ca²⁺-dependent immune cell activation, leukocyte infiltration, and cholesterol accumulation by macrophages promote foam cell formation and atherosclerotic plaque progression. Chronic increases in VSMCs Ca²⁺ promote phenotypic switching to mesenchymal cells and osteogenic transformation and thereby accelerate vascular calcification and plaque instability. Emerging therapeutic strategies targeting these Ca²⁺-dependent mechanisms, including Ca²⁺ channel blockers and PKC and ROCK inhibitors, hold promise for restoring Ca²⁺ homeostasis and mitigating vascular disease progression. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental impairment that occurs due to mutations related to the formation of the nervous system, combined with the impact of various epigenetic and environmental factors. This necessitates the identification of the genetic variations involved in ASD pathogenesis. We performed whole exome sequencing (WES) in a cohort of 22 Bulgarian male and female individuals showing ASD features alongside segregation analyses of their families. A targeted panel of genes was chosen and analyzed for each case, based on a detailed examination of clinical data. Gene analyses revealed that specific variants concern key neurobiological processes involving neuronal architecture, development, and function. These variants occur in a number of genes, including SHANK3, DLG3, NALCN, and PACS2 which are critical for synaptic signaling imbalance, CEP120 and BBS5 for ciliopathies, SPTAN1 for spectrins structure, SPATA5, TRAK1, and VPS13B for neuronal organelles trafficking and integrity, TAF6, SMARCB1, DDX3X, MECP2, and SETD1A for gene expression, CDK13 for cell cycle control, ALDH5A1, DPYD, FH, and PDHX for mitochondrial function, and PQBP1, HUWE1, and WDR45 for neuron homeostasis. Novel single nucleotide variants in the SPATA5, CEP120, BBS5, SETD1A, TRAK1, VPS13B, and DDX3X genes have been identified and proposed for use in ASD diagnostics. Our data contribute to a better understanding of the complex neurobiological features of autism and are applicable in the diagnosis and development of personalized therapeutic approaches. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins and damaged organelles. However, impaired autophagy contributes significantly to AD pathogenesis by disrupting proteostasis, exacerbating neuroinflammation, and promoting synaptic dysfunction. This review aims to scrutinize the intricate relationship between autophagy dysfunction and AD progression, explaining key pathways including macroautophagy, chaperone-mediated autophagy (CMA), and selective autophagy processes such as mitophagy and aggrephagy. This further extends the discussion beyond the central nervous system, evaluating the role of hepatic autophagy in Aβ clearance and systemic metabolic regulation. An understanding of autophagy’s involvement in AD pathology via various mechanisms could give rise to a novel therapeutic strategy targeting autophagic modulation to mitigate disease progression in the future. Full article

Disorders of vesicular trafficking and genetic defects in autophagy play a critical role in the development of metabolic and neurometabolic diseases. These processes govern intracellular transport and lysosomal degradation, thereby maintaining cellular homeostasis. In this article, we present two siblings with a novel homozygous variant in VPS51 (Vacuolar protein sorting 51) gene (c.1511C>T; p.Thr504Met), exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. This study aimed to investigate the effects of the novel VPS51 gene variation at the RNA and protein level in fibroblasts derived from patients. A comparative proteomic analysis, which has not been previously elucidated, was performed to identify uncharacterized proteins associated with vesicular trafficking. Furthermore, the impact of disrupted pathways on mitochondria–lysosome contact sites was assessed, offering a thorough pathophysiological evaluation of GARP/EARP (Golgi Associated Retrograde Protein / Endosome Associated Retrograde Protein) complex dysfunction. An analysis of mRNA expression indicated decreased levels of the VPS51 gene, alongside modifications in the expression of autophagy-related genes (LC3B, p62, RAB7A, TBC1D15). Western blotting demonstrated a reduction in VPS51 and autophagy-related protein levels. Proteomic profiling revealed 585 differentially expressed proteins, indicating disruptions in vesicular trafficking, lysosomal function, and mitochondrial metabolism. Proteins involved in mitochondrial β-oxidation and oxidative phosphorylation exhibited downregulation, whereas pathways related to glycolysis and lipid synthesis showed upregulation. Live-cell confocal microscopy revealed a notable increase in mitochondria–lysosome contact sites in patient fibroblasts, suggesting that VPS51 protein dysfunction contributes to impaired organelle communication. The findings indicate that the novel VPS51 gene variation influences intracellular transport, autophagy, and metabolic pathways, offering new insights into its involvement in neurometabolic disorders. Full article

Mechanical forces are increasingly recognised as fundamental regulators of cellular function, complementing classical biochemical cues to direct development, tissue homeostasis, and disease progression. Cells detect external and internal forces via mechanosensor proteins and adapt their cytoskeletal architecture, leading to changes in cell behaviour. Biomaterials and biodevices come to the aid of tailoring biomaterials’ properties in terms of chemical/physical properties and, by emulating dynamical forces, e.g., shear stress and cell swelling, they may enlighten mechanobiological processes. Additionally, emerging technologies expand the experimental toolkit for probing mechanobiological phenomena in complex, customisable settings. Central to these processes are mechanotransducer proteins and membrane–organelle networks that convert mechanical deformation into biochemical signals, orchestrating downstream transcriptional and post-translational modifications. This review highlights how through bridging material engineering and cellular mechanics, mechanobiology provides a unified framework to understand how physical forces shape tissues and drive pathologies. The continued integration of advanced biomaterials, dynamic biodevices, and multiscale analytical methods promises to uncover new mechanistic insights and inform the development of mechanotherapeutic strategies. Full article

Centrioles are remarkably stable organelles that play a main role in the assembly of centrosomes and ciliary structures. However, there are several differentiated tissues that must eliminate their centrioles to avoid centrosome formation and improper cell proliferation. Therefore, centriole elimination represents an important process in many organisms to ensure successful cell differentiation and maintenance of tissue homeostasis. In this review, we analyzed centriole inactivation and elimination in various Drosophila cell types in relation to the dynamics of the pericentriolar material. Full article

In this manuscript, we highlight the evolutionary origins of mitochondria from bacterial endosymbionts and explore their contributions to health, energy metabolism, and neural–immune communication. Mitochondrial adaptability and the roles played by these organelles in promoting oxygen-dependent ATP production provide critical regulation of cognition, motivation, and inflammation. Hypoxia has been identified as an important initiator of inflammation, neurodegeneration, and mitochondrial dysfunction, emphasizing the overall importance of oxygen homeostasis to health and well-being. The Behavior, Exercise, Relaxation, and Nutrition framework highlights these observations as tools that can be used to optimize mitochondrial efficiency. Interestingly, mitochondrial dysfunction may also be linked to psychiatric disorders (e.g., schizophrenia), a hypothesis that focuses on energy dynamics, a proposal that may extend our understanding of these disorders beyond traditional neurotransmitter-focused concepts. Collectively, these perspectives underscore the critical contributions of mitochondria to health and disease and offer a novel framework that may help to explain the connections featured in mind–body medicine. Full article

Background/Objectives: The autophagy–lysosomal pathway (ALP) is crucial for neuronal health by clearing misfolded proteins and damaged organelles. While much research has focused on ALP dysfunction in the central nervous system, new evidence shows its importance in the gut, where it affects neurodegeneration via the gut–brain axis. Past reviews have mainly studied the ALP’s direct neuroprotective effects or the gut microbiota’s role in neurodegeneration separately. However, the two-way relationship between the ALP and the gut microbiota in neurodegenerative diseases is not well understood. We combine the latest findings on the ALP’s role in gut health, microbial imbalance, and neuroinflammation, providing a comprehensive view of their combined effects in Alzheimer’s, Parkinson’s, and Huntington’s diseases. Methods: This narrative review synthesizes evidence from preclinical, clinical, and translational studies (2014–2025) to explore the interplay between the autophagy–lysosomal pathway (ALP) and the gut–brain axis in neurodegeneration. The literature was identified via PubMed and Web of Science using search terms including autophagy, lysosome, gut microbiota, neurodegeneration, and gut–brain axis, with additional manual screening of reference lists. The inclusion criteria prioritized studies elucidating molecular mechanisms (e.g., ALP–microbiota crosstalk), while excluding case reports or non-peer-reviewed sources. Results: The gut–brain axis facilitates bidirectional communication between the gut and the brain through neural, immune, and metabolic pathways. Autophagy dysfunction may disrupt intestinal homeostasis, promote gut microbiota dysbiosis, and trigger chronic neuroinflammation, ultimately accelerating neurodegeneration. Notably, strategies targeting the gut microbiota and restoring intestinal barrier function via the ALP have demonstrated promising potential in delaying the progression of neurodegenerative diseases. Conclusions: This review establishes the ALP as a dynamic regulator of gut–brain communication, highlighting microbiota-targeted therapies as promising strategies for neurodegeneration. Full article

The term autophagy identifies several mechanisms that mediate the degradation of intracellular and extracellular components via the lysosomal pathway. Three main forms of autophagy exist, namely macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy, which have distinct mechanisms but share lysosomes as the final destination of their cargo. A basal autophagic flux is crucial for the maintenance of cellular homeostasis, being involved in the physiological turnover of proteins and organelles. Several stressors, including nutrient shortage and genotoxic and oxidative stress, increase the autophagic rate, which prevents the accumulation of damaged and potentially harmful cell components, thus preserving cell viability. In this context, several studies have highlighted the role of MAPKs, serine–threonine kinases activated by several stimuli, in linking oxidative stress and autophagy. Indeed, several oxidative stressors activate autophagy by converging on MAPKs, directly or indirectly. In this regard, the different transcription factors that bridge MAPKs and autophagic activation are here described. In this review, we summarize the current knowledge regarding the regulation of autophagy by MAPK, including the atypical ones, with a particular focus on the regulation of autophagy by oxidative stress. Full article