RESUMO
Calcium is a crucial messenger of intracellular and extracellular signals, regulating a great variety of cellular processes such as cell death, proliferation, and metabolism. Inside the cell, calcium signaling is one of the main interorganelle communication mediators, with central functional roles at the endoplasmic reticulum (ER), mitochondria, Golgi complex, and lysosomes. Lysosomal function is highly dependent on lumenal calcium and most of the lysosomal membrane-localised ion channels regulate several lysosomal functions and properties such as lumenal pH. One of these functions configures a specific type of cell death involving lysosomes, named lysosome-dependent cell death (LDCD), which contributes to maintenance of tissue homeostasis, development and pathology when deregulated. Here, we cover the fundamental aspects of LDCD with a special focus on recent advances in calcium signaling in LDCD.
Assuntos
Sinalização do Cálcio , Cálcio , Cálcio/metabolismo , Morte Celular , Lisossomos/metabolismo , Membranas Intracelulares/metabolismoRESUMO
The appreciation of the importance of interorganelle contacts has steadily increased over the past decades. Advances in imaging, molecular biology and bioinformatic techniques allowed the discovery of new mechanisms involved in the interaction and communication between organelles, providing novel insights into the inner works of a cell. In this Review, with the mitochondria under the spotlight, we discuss the most recent findings on the mechanisms mediating the communication between organelles, focusing on Ca2+ signaling, lipid exchange, cell death and stress responses. Notably, we introduce a new integrative perspective to signaling networks that is regulated by interorganelle interactions - the mitochondria-associated niches - focusing on the link between the molecular determinants of contact sites and their functional outputs, rather than simply physical and structural communication. In addition, we highlight the neuropathological and metabolic implications of alterations in mitochondria-associated niches and outline how this concept might improve our understanding of multi-organelle interactions.
Assuntos
Mitocôndrias , Membranas Mitocondriais , Morte Celular , Transdução de Sinais , Biologia ComputacionalRESUMO
Current monitoring of acute lymphoblastic leukemia (ALL) in living mice is based on FACS analysis of blood hCD45+ cells. In this work, we evaluated the use of human IGFBP2, B2M or Hsp90 as soluble markers of leukemia. ELISA for B2M and IGFBP2 resulted in high background levels in healthy animals, precluding its use. Conversely, plasma levels of Hsp90 showed low background and linear correlation to FACS results. In another experiment, we compared Hsp90 levels with percentage of hCD45+ cells in blood, bone marrow, liver and spleen of animals weekly sacrificed. Hsp90 levels proved to be a superior method for the earlier detection of ALL engraftment and correlated linearly to ALL burden and progression in all compartments, even at minimal residual disease levels. Importantly, the Hsp90/hCD45+ ratio was not altered when animals were treated with dexamethasone or a PI3K inhibitor, indicating that chemotherapy does not directly interfere with leukemia production of Hsp90. In conclusion, plasma Hsp90 was validated as a soluble biomarker of ALL, useful for earlier detection of leukemia engraftment, monitoring leukemia kinetics at residual disease levels, and pre-clinical or mouse avatar evaluations of anti-leukemic drugs.