Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(3), С. 223 - 245

Опубликована: Ноя. 24, 2023

Язык: Английский

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Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Frontiers in Physiology, Год журнала: 2021, Номер 12

Опубликована: Апрель 9, 2021

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in weakness, respiratory cardiac failure, premature death. There no curative treatment. Investigations on disease-causing mechanisms offer opportunity to identify new therapeutic targets treat DMD. An abnormal elevation intracellular calcium ( Cai2+ ) concentration dystrophin-deficient a major secondary event, which contributes progression Emerging studies have suggested that targeting Ca 2+ -handling proteins and/or could be promising strategy for Here, we provide updated overview mechanistic roles sarcolemma, sarcoplasmic/endoplasmic reticulum, mitochondria play sustained id="M2">Cai2+ levels their involvement pathogenesis. We also discuss current approaches aimed at restoring homeostasis as potential therapies

Язык: Английский

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Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway

Autophagy, Год журнала: 2021, Номер 18(8), С. 1932 - 1954

Опубликована: Дек. 8, 2021

Compelling evidence has demonstrated that macroautophagy/autophagy plays an important role in regulating multiple steps of metastatic cascades; however, the precise autophagy metastasis remains unclear. This study demonstrates inhibition induced by MCOLN1/TRPML1 suppresses cancer evoking ROS-mediated TP53/p53 pathway. First, we found MCOLN1-mediated not only profoundly inhibits both migration and invasion malignant melanoma glioma cell lines vitro, but also vivo. Second, our reveals MCOLN1 leads to damaged mitochondria accumulation followed large quantities ROS release. Third, demonstrate elevated resulting from subsequently triggers TP53 activity, which turn modulates expression its downstream targets are involved a broad spectrum cascade suppress including MMP members TWIST. In summary, findings have established mechanism via ROS-TP53 signaling More importantly, through stimulation could evidently be one therapeutic potentials for combating metastasis.

Язык: Английский

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Lysosomal Zn2+ release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma

Cell Reports, Год журнала: 2021, Номер 37(3), С. 109848 - 109848

Опубликована: Окт. 1, 2021

Highlights•TRPML1 is dramatically upregulated in metastatic melanoma cells•Activation of TRPML1, instead inhibition, induces selective cell death•TRPML-specific synthetic agonists (ML-SAs) trigger a distinctive form death•ML-SAs exhibit potent vivo therapeutic efficacy advanced mouse modelsSummaryDuring tumor progression, lysosome function often maladaptively to match the high energy demand required for cancer hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), lysosomal Ca2+ Zn2+ release regulates multiple aspects function, cells compared with normal cells. TRPML-specific are sufficient induce rapid (within hours) Zn2+-dependent necrotic death while completely sparing ML-SA-caused mitochondria swelling dysfunction lead cellular ATP depletion. While pharmacological inhibition or genetic silencing TRPML1 prevents such death, overexpression confers ML-SA vulnerability. In models, ML-SAs suppressing progression. Hence, targeting machinery can selectively eradicate vitro vivo.Graphical abstract

Язык: Английский

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Duchenne muscular dystrophy: pathogenesis and promising therapies

Journal of Neurology, Год журнала: 2023, Номер 270(8), С. 3733 - 3749

Опубликована: Июнь 1, 2023

Язык: Английский

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The ion channels of endomembranes

Physiological Reviews, Год журнала: 2024, Номер 104(3), С. 1335 - 1385

Опубликована: Март 7, 2024

The endomembrane system consists of organellar membranes in the biosynthetic pathway [endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles] as well those degradative (early endosomes, macropinosomes, phagosomes, autophagosomes, late lysosomes). These organelles/vesicles work together to synthesize, modify, package, transport, degrade proteins, carbohydrates, lipids, regulating balance between cellular anabolism catabolism. Large ion concentration gradients exist across endomembranes: Ca 2+ for most organelles H + acidic compartments. Ion (Na , K Cl − ) channels on control flux response cues, allowing rapid informational exchange cytosol organelle lumen. Recent advances proteomics, electrophysiology, luminal juxtaorganellar imaging have led molecular identification functional characterization about two dozen channels. For example, whereas IP3R1–3 mediate release from ER neurotransmitter hormone stimulation, TRPML1–3 TMEM175 lysosomal release, respectively, nutritional trafficking cues. This review aims summarize current understanding these channels, with a focus their subcellular localizations, permeation properties, gating mechanisms, cell biological functions, disease relevance.

Язык: Английский

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Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism

Nature Aging, Год журнала: 2024, Номер 4(5), С. 647 - 663

Опубликована: Апрель 22, 2024

Язык: Английский

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MCOLN1/TRPML1 in the lysosome: a promising target for autophagy modulation in diverse diseases

Autophagy, Год журнала: 2024, Номер 20(8), С. 1712 - 1722

Опубликована: Март 24, 2024

MCOLN1/TRPML1 is a nonselective cationic channel specifically localized to the late endosome and lysosome. With its property of mediating release several divalent cations such as Ca2+, Zn2+ Fe2+ from lysosome cytosol, MCOLN1 plays pivotal role in regulating variety cellular events including endocytosis, exocytosis, lysosomal biogenesis, reformation, especially Macroautophagy/autophagy. Autophagy highly conserved catabolic process that maintains cytoplasmic integrity by removing superfluous proteins damaged organelles. Acting terminal compartments, lysosomes are crucial for completion autophagy process. This review delves into emerging controlling autophagic ionic homeostasis, thereby governing fundamental functions lysosomes. Furthermore, this summarizes physiological relevance well molecular mechanisms through which orchestrates autophagy, consequently influencing mitochondria turnover, cell apoptosis migration. In addition, we have illustrated implications MCOLN1-regulated pathological cancer myocardial ischemia-reperfusion (I/R) injury. summary, given involvement MCOLN1-mediated pathogenesis I/R injury, targeting May provide clues developing new therapeutic strategies treatment these diseases. Exploring regulation diverse diseases contexts will surely broaden our understanding pathway offer potential promising drug target.

Язык: Английский

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Ca ²⁺ -sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(22)

Опубликована: Май 23, 2024

Lysosomes are central players in cellular catabolism, signaling, and metabolic regulation. Cellular environmental stresses that damage lysosomal membranes can compromise their function release toxic content into the cytoplasm. Here, we examine how cells respond to osmotic stress within lysosomes. Using sensitive assays of leakage rupture, acute effects disruptant glycyl-L-phenylalanine 2-naphthylamide (GPN). Our findings reveal low concentrations GPN rupture a small fraction lysosomes, but surprisingly trigger Ca 2+ from nearly all. Chelating cytoplasmic makes lysosomes more GPN-induced suggesting role for membrane resilience. GPN-elicited causes -sensor Apoptosis Linked Gene-2 (ALG-2), along with Endosomal Sorting Complex Required Transport (ESCRT) proteins it interacts with, redistribute onto Functionally, ALG-2, not its ESCRT binding-disabled ΔGF 122 splice variant, increases resilience stress. Importantly, elevating juxta-lysosomal without by activating TRPML1 also recruits ALG-2 ESCRTs, protecting subsequent rupture. These , through helps bring ESCRTs enhance maintain organelle integrity face

Язык: Английский

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Lysosomal solute and water transport

The Journal of Cell Biology, Год журнала: 2022, Номер 221(11)

Опубликована: Сен. 23, 2022

Lysosomes mediate hydrolase-catalyzed macromolecule degradation to produce building block catabolites for reuse. Lysosome function requires an osmo-sensing machinery that regulates osmolytes (ions and organic solutes) water flux. During hypoosmotic stress or when undigested materials accumulate, lysosomes become swollen hypo-functional. As a membranous organelle filled with cargo macromolecules, catabolites, ions, hydrolases, the lysosome must have mechanisms regulate its shape size while coordinating content exchange. In this review, we discussed lysosomal fusion fission as well swelling condensation, focus on solute transport across membranes. Lysosomal H+, Na+, K+, Ca2+, Cl− channels transporters sense trafficking osmotic cues both flux membrane trafficking. We also provide perspectives how may adjust volume of themselves, cytosol, cytoplasm through control transport.

Язык: Английский

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