Lysosome calcium in ROS regulation of autophagy.
TL;DR: A lysosomal signaling mechanism for cells to respond to oxidative bursts and adapt to oxidative stress is revealed, which may induce autophagy by activating the MCOLN1-lysosome Ca2+-TFEB pathway.
Abstract: Lysosomes, the cell's recycling center, undergo nutrient-sensitive adaptive changes in function and biogenesis, i.e., lysosomal adaptation. We recently discovered that lysosomes also mediate the cell's "survival" response (i.e., autophagy) to oxidative stress through the activation of TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy. MCOLN1/TRPML1, the principal Ca2+ release channel on the lysosomal membrane, serves as the redox sensor in this process. Increasing reactive oxygen species (ROS) levels, either endogenously by mitochondrial damage or exogenously, directly activates MCOLN1 to induce lysosomal Ca2+ release, triggering PPP3/calcineurin-dependent TFEB nuclear translocation to enhance autophagy. Hence, ROS may induce autophagy by activating the MCOLN1-lysosome Ca2+-TFEB pathway, facilitating the removal of damaged mitochondria and excess ROS. Our findings have revealed a lysosomal signaling mechanism for cells to respond to oxidative bursts and adapt to oxidative stress.
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04 Jan 2021
TL;DR: Kim et al. as discussed by the authors conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an auto-generative enhancer.
Abstract: Disorders of autophagy, a key regulator of cellular homeostasis, cause a number of human diseases. Due to the role of autophagy in metabolic dysregulation, there is a need to identify autophagy regulators as therapeutic targets. To address this need, we conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an autophagy enhancer. Kaem promoted autophagy through translocation of transcription factor EB (TFEB) without MTOR perturbation, suggesting it is safe for administration. Moreover, Kaem accelerated lipid droplet degradation in a lysosomal activity-dependent manner in vitro and ameliorated metabolic dysregulation in a diet-induced obesity mouse model. To elucidate the mechanism underlying Kaem’s biological activity, the target protein was identified via combined drug affinity responsive target stability and LC–MS/MS analyses. Kaem directly interacted with the mitochondrial elongation factor TUFM, and TUFM absence reversed Kaem-induced autophagy and lipid degradation. Kaem also induced mitochondrial reactive oxygen species (mtROS) to sequentially promote lysosomal Ca2+ efflux, TFEB translocation and autophagy induction, suggesting a role of TUFM in mtROS regulation. Collectively, these results demonstrate that Kaem is a potential therapeutic candidate/chemical tool for treating metabolic dysregulation and reveal a role for TUFM in autophagy for metabolic regulation with lipid overload. Kim, Hwang et al. use in vitro and in vivo models of autophagy disorder/metabolic dysfunction to show that in this context, the natural compound kaempferide is an autophagy enhancer and reveal that one of the underlying mechanisms governing this is mediated by the mitochondrial elongation factor TUFM. This insight may have therapeutic value in the treatment of metabolic disorders.
121 citations
TL;DR: The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.
Abstract: Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby stimulating core metabolic pathways, but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mTOR inhibition or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and therefore impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the SERCA Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER-mitochondria Ca2+ fueling, IP3R inhibition lead to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against NK cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis therefore directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.
117 citations
Cites background from "Lysosome calcium in ROS regulation ..."
...Recently, it was shown that TRMPL1 can serve as a redox status sensor and can release Ca2+ upon stimulation by ROS or by mitochondrial uncouplers (91, 92)....
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TL;DR: Cancer-associated alterations of Ca2+ fluxes at specific organelles are discussed as novel candidates for the development of drugs that selectively target Ca2- signaling in malignant cells are identified.
115 citations
TL;DR: Redox regulated events that are disrupted in neurodegenerative disorders and whose modulation affords therapeutic opportunities are reviewed and may provide avenues for novel therapeutics.
Abstract: Significance: Once considered to be mere by-products of metabolism, reactive oxygen, nitrogen and sulfur species are now recognized to play important roles in diverse cellular processes su...
83 citations
TL;DR: Wang et al. as discussed by the authors investigated the involvement of lysosome function and ferroptosis in the anti-cancer potential of quercetin, and they found that quercETin is known to promote p53-independent cell death in various cancer cell lines.
Abstract: Background and purpose Cancer cells exhibit more dependence on iron and enhanced sensitivity to iron-dependent, programmed cell death (ferroptosis) than normal cells. Quercetin exerts anti-cancer effects, but the underlying molecular mechanism is largely unknown. In this study, we aimed to investigate the involvement of lysosome function and ferroptosis in the anti-cancer potential of quercetin. Experimental approach We used MTT assays and DNA content analysis to evaluate the cytotoxicity, colony formation assay to investigate cell proliferation, and flow cytometry and confocal microscopy to detect lysosomal acidification and protease enzyme activity. Western blotting, cell subfractionation, RT-PCR and siRNA transfection were used to establish molecular mechanisms of action. Key results Quercetin is known to promote p53-independent cell death in various cancer cell lines. Although quercetin induces autophagy, genetic silencing of Atg7 fails to affect quercetin-induced cell death. In contrast, both lysosome inhibitors and knockdown of the transcription factor EB can prevent quercetin-induced cell death, suggesting the involvement of lysosome. Next, quercetin is found to induce lysosomal activation sequentially through nuclear translocation of EB and transcriptional activation of lysosomal genes. Notably, quercetin promoted lysosome-dependent ferritin degradation and free iron release. This action and quercetin-induced ROS generation synergistically resulted in lipid peroxidation and ferroptosis. Furthermore, Bid may link ferroptosis with apoptosis to cause cell death. Conclusion and implications Quercetin induced EB-mediated lysosome activation and increased ferritin degradation leading to ferroptosis and Bid-involved apoptosis. Results from this study may expand our current knowledge about the mechanism of quercetin as an anti-cancer agent.
79 citations