bims-lypmec 2024-05-12 papers

Front Cell Dev Biol. 2024 ;12 1386149

Golgi defect as a major contributor to lysosomal dysfunction.

The Golgi apparatus plays a crucial role in lysosome biogenesis and the delivery of lysosomal enzymes, essential for maintaining cellular homeostasis and ensuring cell survival. Deficiencies in Golgi structure and function can profoundly impact lysosomal homeostasis, leading to various lysosomal storage diseases and neurodegenerative disorders. In this review, we highlight the role of the Golgi Reassembly Stacking Proteins (GRASPs) in the formation and function of the Golgi apparatus, emphasizing the current understanding of the association between the Golgi apparatus, lysosomes, and lysosomal storage diseases. Additionally, we discuss how Golgi dysfunction leads to the secretion of lysosomal enzymes. This review aims to serve as a concise resource, offering insights into Golgi structure, function, disease-related defects, and their consequential effects on lysosomal biogenesis and function. By highlighting Golgi defects as an underappreciated contributor to lysosomal dysfunction across various diseases, we aim to enhance comprehension of these intricate cellular processes.

Keywords: GRASP55; GRASP65; Golgi; HexA; lysosomal storage diseases; lysosome; neurodegenerative diseases; secretion

DOI: https://doi.org/10.3389/fcell.2024.1386149

Med Res Rev. 2024 May 06.

Targeting lysosomal quality control as a therapeutic strategy against aging and diseases.

Yuchen He, Yishu Fan, Xenab Ahmadpoor, Yumin Wang, Zhong Alan Li, Weihong Zhu, Hang Lin.

Previously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded the lysosomal functional scope and revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, and cellular stress response. Lysosomal dysfunction is also found to be associated with aging and several diseases. Therefore, function of macroautophagy, a lysosome-dependent intracellular degradation system, has been identified as one of the updated twelve hallmarks of aging. In this review, we begin by introducing the concept of lysosomal quality control (LQC), which is a cellular machinery that maintains the number, morphology, and function of lysosomes through different processes such as lysosomal biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, and membrane permeabilization and repair. Next, we summarize the results from studies reporting the association between LQC dysregulation and aging/various disorders. Subsequently, we explore the emerging therapeutic strategies that target distinct aspects of LQC for treating diseases and combatting aging. Lastly, we underscore the existing knowledge gap and propose potential avenues for future research.

Keywords: aging; autoimmune diseases; cancer; degenerative diseases; lysosomal quality control

DOI: https://doi.org/10.1002/med.22047

Front Immunol. 2024 ;15 1393852

Independent organelle and organelle-organelle interactions: essential mechanisms for malignant gynecological cancer cell survival.

Ying Shen, Qiao-Chu Chen, Chen-Yu Li, Feng-Juan Han.

Different eukaryotic cell organelles (e.g., mitochondria, endoplasmic reticulum, lysosome) are involved in various cancer processes, by dominating specific cellular activities. Organelles cooperate, such as through contact points, in complex biological activities that help the cell regulate energy metabolism, signal transduction, and membrane dynamics, which influence survival process. Herein, we review the current studies of mechanisms by which mitochondria, endoplasmic reticulum, and lysosome are related to the three major malignant gynecological cancers, and their possible therapeutic interventions and drug targets. We also discuss the similarities and differences of independent organelle and organelle-organelle interactions, and their applications to the respective gynecological cancers; mitochondrial dynamics and energy metabolism, endoplasmic reticulum dysfunction, lysosomal regulation and autophagy, organelle interactions, and organelle regulatory mechanisms of cell death play crucial roles in cancer tumorigenesis, progression, and response to therapy. Finally, we discuss the value of organelle research, its current problems, and its future directions.

Keywords: endoplasmic reticulum; lysosome; malignant gynecological cancer; mitochondria; organelle

DOI: https://doi.org/10.3389/fimmu.2024.1393852

iScience. 2024 May 17. 27(5): 109735

Glucose starvation causes ferroptosis-mediated lysosomal dysfunction.

Kenji Miki, Mikako Yagi, Dongchon Kang, Yuya Kunisaki, Koji Yoshimoto, Takeshi Uchiumi.

Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases.

Keywords: Cell biology; Cellular physiology; Functional aspects of cell biology

DOI: https://doi.org/10.1016/j.isci.2024.109735

J Pharm Pharm Sci. 2024 ;27 12568

Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy.

Michinari Nakamura.

Unhealthy sources of fats, ultra-processed foods with added sugars, and a sedentary lifestyle make humans more susceptible to developing overweight and obesity. While lipids constitute an integral component of the organism, excessive and abnormal lipid accumulation that exceeds the storage capacity of lipid droplets disrupts the intracellular composition of fatty acids and results in the release of deleterious lipid species, thereby giving rise to a pathological state termed lipotoxicity. This condition induces endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory responses, and cell death. Recent advances in omics technologies and analytical methodologies and clinical research have provided novel insights into the mechanisms of lipotoxicity, including gut dysbiosis, epigenetic and epitranscriptomic modifications, dysfunction of lipid droplets, post-translational modifications, and altered membrane lipid composition. In this review, we discuss the recent knowledge on the mechanisms underlying the development of lipotoxicity and lipotoxic cardiometabolic disease in obesity, with a particular focus on lipotoxic and diabetic cardiomyopathy.

Keywords: cardiometabolic disease; diabetes; diabetic cardiomyopathy; heart failure; inflammation; lipotoxic cardiomyopathy; lipotoxicity; obesity

DOI: https://doi.org/10.3389/jpps.2024.12568