Coxiella burnetii effector CvpE maintains biogenesis of Coxiella -containing vacuoles by suppressing lysosome tubulation through binding PI(3)P and perturbing PIKfyve activity on lysosomes DOI Creative Commons
Mingliang Zhao, Shan Zhang,

Weiqiang Wan

et al.

Virulence, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 9, 2024

Coxiella burnetii (C. burnetii) is the causative agent of Q fever, a zoonotic disease. Intracellular replication C. requires maturation phagolysosome-like compartment known as permissive Coxiella-containing vacuole (CCV). Effector proteins secreted by Dot/Icm secretion system are indispensable for single large CCV facilitating fusion promiscuous vesicles. However, mechanisms maintenance and evasion host cell clearance remain to be defined. Here, we show that vacuolar protein E (CvpE) contributes biogenesis inducing lysosome-like (LLV) enlargement. LLV fission tubulation autolysosome degradation impaired in CvpE-expressing cells. Subsequently, found CvpE suppresses lysosomal Ca2+ channel transient receptor potential mucolipin 1 (TRPML1) activity an indirect manner, which binds phosphatidylinositol 3-phosphate [PI(3)P] perturbs PIKfyve lysosomes. Finally, agonist TRPML1, ML-SA5, inhibits replication. These results provide insight into suggest TRPML1 can novel treatment does not rely on antibiotics fever enhancing vacuoles (CCVs) fission.

Language: Английский

Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology DOI
Carmine Settembre, Rushika M. Perera

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 223 - 245

Published: Nov. 24, 2023

Language: Английский

Citations

95
Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies DOI Creative Commons
Satvik Mareedu,

Emily D. Million,

Dongsheng Duan

et al.

Frontiers in Physiology, Journal Year: 2021, Volume and Issue: 12

Published: April 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

Language: Английский

Citations

95
Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway DOI Open Access

Yanhong Xing,

Xiangqing Wei,

Yucheng Liu

et al.

Autophagy, Journal Year: 2021, Volume and Issue: 18(8), P. 1932 - 1954

Published: Dec. 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.

Language: Английский

Citations

94
Lysosomal Zn2+ release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma DOI Creative Commons
Wanlu Du, Mingxue Gu, Meiqin Hu

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 37(3), P. 109848 - 109848

Published: Oct. 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

Language: Английский

Citations

69
Duchenne muscular dystrophy: pathogenesis and promising therapies DOI

Mengyuan Chang,

Yong Cai,

Zihui Gao

et al.

Journal of Neurology, Journal Year: 2023, Volume and Issue: 270(8), P. 3733 - 3749

Published: June 1, 2023

Language: Английский

Citations

27
The ion channels of endomembranes DOI
Meiqin Hu, Xinghua Feng, Qiang Liu

et al.

Physiological Reviews, Journal Year: 2024, Volume and Issue: 104(3), P. 1335 - 1385

Published: March 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.

Language: Английский

Citations

13
Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism DOI
Zhiwen Deng, Liangyu Zhao, Sha Li

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(5), P. 647 - 663

Published: April 22, 2024

Language: Английский

Citations

13
MCOLN1/TRPML1 in the lysosome: a promising target for autophagy modulation in diverse diseases DOI

Jiansong Qi,

Qingqing Li,

Tianli Xin

et al.

Autophagy, Journal Year: 2024, Volume and Issue: 20(8), P. 1712 - 1722

Published: March 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.

Language: Английский

Citations

10
Ca 2+ -sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress DOI Creative Commons
W. Chen,

Madeline M. Motsinger,

Jiaqian Li

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(22)

Published: May 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

Language: Английский

Citations

10
Lysosomal solute and water transport DOI Creative Commons
Meiqin Hu, Nan Zhou, Weijie Cai

et al.

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(11)

Published: Sept. 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.

Language: Английский

Citations

34