PubMed · 559022
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
T Takano. 1977. [Lysosomes].. https://pubmed.ncbi.nlm.nih.gov/559022/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.
Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders.
Most of the cationic amphiphilic drugs (CAD) exert their pharmacological effect through specific receptors which are of protein origin. These interactions result from a sufficiently tight and time dependent binding of CAD to the cell surface transmitting chemical signals into biological effects. For such events each cell is equipped with a wide variety of second messengers. Yet the chemical structure of CAD and biophysical composition of biological membranes enable interactions with corresponding structures without primarily activating the receptor. As a rule such interactions bring about a response characterised as side effect of the individual drug, which might not be equal to the adverse reaction. Nevertheless, these interactions may result also in adverse and toxic responses to the drugs administered. The nonreceptor interactions between CAD, cells, tissues, organs and the whole organism depend on the physico-chemical nature of these drugs and their ability to enter and pass through the plasma membrane on the one side, and on the biological properties of membrane phospholipids and their integral components, on the other. The structure, synthesis, turnover and metabolism of membrane phospholipids play an important role in these processes. Along with A2 and C phospholipases, membrane phospholipids are also donators of the most important second messengers participating in the control of cell functions, such as signal transmission, contraction and relaxation of muscles, cell aggregation, secretion, phagocytosis. CAD are capable to initiate a biological response bypassing specific receptors, interfering thus with the functional structure of membrane phospholipids. This effect is time-dependent and dose-dependent and besides the above mentioned changes in cell functions, CAD can initiate induction of phospholipidoses and nonspecific toxic effects. Further detailed experimental and clinical studies are required to provide full understanding of the interactions between CAD and changes induced in the lipid, protein and carbohydrate cell structures of individual cells and tissues.