A cation counterflux supports lysosomal acidification

Steinberg, Benjamin E.; Huynh, Kassidy K.; Brodovitch, Alexandre; Jabs, Sabrina; Stauber, Tobias; Jentsch, Thomas J.; Grinstein, Sergio

doi:10.1085/jgp1362oia2

Cited by 29 publications

(52 citation statements)

References 28 publications

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“…Endolysosomal pH measurements were performed by ratiometric fluorescence imaging as described previously 56 . MEFs were seeded on imaging dishes (145 mm glass bottom, PAA Laboratories, Germany) and grown overnight in DMEM supplemented with 1 g l À 1 bovine serum albumin in the presence of 500 mg ml À 1 of the pH-sensitive fluorophore Oregon Green 514 conjugated to dextran (70,000 MW, Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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Section: Methodsmentioning

confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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“…NHEs) and counterion conductances (e.g. Cl -channels) [39,156]. Due to their distinct localization to specific types of organelles it is likely that intracellular NHEs play a critical part in the regulation of organellar pH.…”

Section: Intracellular Nhesmentioning

confidence: 99%

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Fuster

Alexander

2013

Pflugers Arch - Eur J Physiol

141

122

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The SLC9 gene family encodes Na + /H + exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [46,22,128]. The SLC9 gene family (solute carrier classification of transporters:www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46].NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na + and HCO 3 -and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease.However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.

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“…An idealisation we used in the simulations is that we assumed that the given fraction (0, 25,50 or 100%) of cells that were arrested when they reached a checkpoint was constant in time.…”

Section: 9mentioning

confidence: 99%

“…24 It has been proposed that the effect of cationic nanoparticles on lysosomes could be due to a mechanism called the proton sponge in which the amine groups on the nanoparticles' surface get protonated inside the acidic organelles and increase the osmotic pressure of the vesicles due to the internalisation of neutralising ions and water. [48][49][50] However, data on non-protonable cationic nanoparticles suggest that protonation alone would not be enough to account for nanoparticleinduced lysosomal damage. 23,24 In order to further study the observed swelling and investigate if lysosomal membrane permeability was compromised in the exposure conditions applied here, PS-NH 2 -treated cells were stained with the acidotropic dye LysoTracker Red (Fig.…”

Section: 9mentioning

confidence: 99%

Low Dose of Amino-Modified Nanoparticles Induces Cell Cycle Arrest

et al. 2013

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The interaction of nanoscaled materials with biological systems is currently the focus of a fast-growing area of investigation. Though many nanoparticles interact with cells without acute toxic responses, amino-modified polystyrene nanoparticles are known to induce cell death. We have found that by lowering their dose, cell death remains low for several days while, interestingly, cell cycle progression is arrested. In this scenario, nanoparticle uptake, which we have recently shown to be affected by cell cycle progression, develops differently over time due to the absence of cell division. This suggests that the same nanoparticles can trigger different pathways depending on exposure conditions and the dose accumulated.

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A cation counterflux supports lysosomal acidification

Cited by 29 publications

References 28 publications

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

Low Dose of Amino-Modified Nanoparticles Induces Cell Cycle Arrest

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