Trends in Cell Biology最新文献

Cholesterol is an essential lipid component of membrane bilayers that maintains proper cellular function. Macrophages, key innate immune cells, are involved in organ development, tissue repair, defense against infection, and tumor progression. Accumulating evidence indicates that macrophages undergo significant reprogramming of cholesterol metabolism in response to external signals from diverse pathological microenvironments. This review provides a comprehensive overview of the cellular and systemic regulation of cholesterol metabolism homeostasis and examines how cholesterol metabolites regulate macrophage function. It highlights recent advances in targeting cholesterol metabolism for therapeutic purposes in various human diseases, including neurodegenerative diseases, atherosclerosis, bacterial and viral infections, and cancer.

Membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) are essential for lipid transfer, calcium signaling, and membrane organization. While the formation and function of ER-PM contacts are increasingly well-characterized, the spatiotemporal regulation of their localization remains elusive. Emerging evidence using nanopatterned substrates, ultrastructural imaging, and protein localization analyses indicates that membrane curvature can act as a spatial cue for the recruitment of specific tethering proteins, influencing where contact sites form. This opinion article synthesizes recent advances linking membrane topography ER-PM contact organization and highlights systems where curvature actively orchestrates contact position through curvature-sensing proteins. It also outlines key unanswered questions about how membrane curvature integrates into broader signaling networks that govern organelle contact communication.

Red blood cell (RBC) production, or erythropoiesis, serves as a paradigm for studying cellular differentiation in both physiological and pathological contexts. While the transcriptional and epigenetic programs controlling erythropoiesis are well characterized, the metabolic regulation of this complex process remains underexplored. Recent discoveries that pyruvate kinase activators improve outcomes in sickle cell disease and thalassemia underscore the therapeutic potential of targeting metabolism in RBC disorders. However, further progress is limited by an incomplete understanding of the metabolic networks supporting erythropoiesis and RBC function. This review highlights emerging insights into erythroid metabolic reprogramming involving bioenergetic and biosynthetic processes, newly discovered pathways shaping the erythroid metabolome, and the promise and challenges of exploiting metabolic vulnerabilities in inherited and acquired red cell disorders.

Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.

While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.

Mechanotransduction is the process by which cells detect mechanical forces and convert them into biochemical or electrical signals. This process occurs across various cellular compartments, including the plasma membrane, cytoskeleton, and intracellular organelles. While research has focused mainly on force sensing at the plasma membrane, the mechanisms and significance of intracellular mechanotransduction are just beginning to be understood. This review summarizes current techniques for studying organellar mechanobiology, and highlights advances in our understanding of the mechanosensitive events occurring in organelles such as the endoplasmic reticulum (ER), Golgi apparatus, and endolysosomes. Additionally, some open questions and promising directions are identified for future research.

Acute myeloid leukemia (AML) is an aggressive hematological cancer with a 70% five-year mortality rate. Relapse occurs in approximately half of adults treated with intensive chemotherapy, while responses to targeted therapies are short-lasting. Frequent mutations in signaling pathways, such as FLT3 tyrosine kinase and RAS, lead to dysregulated mammalian target of rapamycin complex 1 (mTORC1)and mitogen-activated protein kinase (MAPK) signaling, increased protein synthesis, enhanced mitochondrial fitness, and metabolic adaptations that drive leukemic cell proliferation and survival. Here, emerging evidence supporting the unique role of eukaryotic initiation factor 4F as a key driver of the expression of proteins regulating leukemic cell metabolism and survival and the potential therapeutic benefit of targeting this pathway pharmacologically in AML are discussed.

Cancer evolution is driven by molecular events within cancer cells and their complex interactions with surrounding cells. Intra-tumor heterogeneity - driven by somatic genetic mutations, epigenetic dysregulation, immune cell infiltration, and microenvironmental factors - complicates the identification of reliable biomarkers and therapeutic targets. Single-cell sequencing and spatial multiomics technologies are revolutionizing our comprehension of how each component of the cellular machinery and tissue architecture collaborates to propel cancer progression. Much like how the restoration and interpretation of Pompeii mosaics have enriched our understanding of ancient Roman life, unraveling the intricate mosaic of cancer will transform the way this disease is diagnosed and treated. This review describes how the advent of single-cell multiomics has provided crucial insights into cutaneous melanoma biology and the mechanisms underlying resistance to immunotherapy.

The blood-brain barrier, recently reintroduced as the blood-brain border (BBB), is a dynamic interface between the central nervous system (CNS) and the bloodstream. Disruption of the BBB exposes the CNS to peripheral pathogens and harmful substances, causing or worsening various CNS diseases. While traditional views attribute BBB failure to tight junction disruption or increased transcytosis, recent studies highlight the critical role of gasdermin D (GSDMD) pore formation in brain endothelial cells (bECs) during BBB disruption by lipopolysaccharide (LPS) or bacterial infections. This mechanism may also be involved in neurological complications like the 'brain fog' seen in long COVID. Pore formation in bECs may represent a prevalent mechanism causing BBB leakage. Investigating membrane-permeabilizing pores or channels and their effects on BBB integrity is a growing area of research. Further exploration of molecular processes that maintain, disrupt, and restore bEC membrane integrity will advance our understanding of brain vasculature and aid in developing new therapies for BBB-related diseases.

Stem cell-based embryo models provide an alternative system to study an elusive period of development. Programmed mouse embryo models have recently been generated by activating two endogenous regulatory elements via epigenome editing. In this forum article, we discuss this achievement along with the potential of translating it to engineering models of human embryogenesis.