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An SLC12A9-dependent ion transport mechanism regulates lysosomal osmolarity

ABSTRACT: An SLC12A9-dependent ion transport mechanism regulates lysosomal osmolarity

PROVIDER: PRJNA1158457 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30593831_1.fastq.gz	Fastqsanger.gz
	SRR30593831_2.fastq.gz	Fastqsanger.gz
	SRR30593832_1.fastq.gz	Fastqsanger.gz
	SRR30593832_2.fastq.gz	Fastqsanger.gz
	SRR30593833_1.fastq.gz	Fastqsanger.gz

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An SLC12A9-dependent ion transport mechanism regulates lysosomal osmolarity

Project description:Ammonia is a ubiquitous, toxic by-product of cell metabolism. Its high membrane permeability and proton affinity causes ammonia to accumulate inside acidic lysosomes in its poorly membrane-permeant form: ammonium (NH4+). Ammonium buildup compromises lysosomal function, suggesting the existence of mechanisms that protect cells from ammonium toxicity. Here, we identified SLC12A9 as a lysosomal regulator of ammonium export that preserves lysosomal homeostasis. SLC12A9 knockout cells showed grossly enlarged lysosomes and elevated ammonium content. These phenotypes were reversed upon removal of the metabolic source of ammonium or dissipation of the lysosomal pH gradient. Lysosomal chloride increased in SLC12A9 knockout cells and chloride binding by SLC12A9 was required for ammonium transport. Our data indicate that SLC12A9 function is central for the handling of lysosomal ammonium and chloride, an unappreciated, fundamental mechanism of lysosomal physiology that may have special relevance in tissues with elevated ammonia, such as tumors.

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Astaburuaga2019 - ODE model of lysosomal ion homeostasis (LIH) including calcium pathways

Project description:To investigate the putative differential effect of chloride transport on lysosomal ion homeostasis,we generated an ODE mathematical model for this system. Our mathematical model builds upon a previously published model for lysosomal homeostasis (Grabe et al. 2001 J. Gen. Physiol, Ishida et al. 2013 J. Gen. Physiol), and further includes the (de)activation kinetics of the ClC-7 antiporter and Ca2+ uptake/release mechanisms. Our new model tracks the total number of ions within the lysosomal lumen over time. It considers different types of lysosomal ion channels and exchangers and two possible lysosomal Ca2+ transporters. The variation in the total number of each ion within the lysosome is described by an ordinary differential equation (ODE), and the rate of change is determined by the flux of the corresponding ion across the lysosomal membrane. The model considers different elements affecting lysosomal ion homeostasis, among which are: (i) the V-ATPase pump, (ii) a proton leak, (iii) the luminal proton buffering capacity, (iv) ClC-7 chloride/proton exchanger, (v) Ca2+ /proton exchanger (CAX), (vi) passive channels for K+ , Na+ , and Ca2+ , and (vii) Donnan particles, which are negatively charged particles or molecules trapped in the lysosomal lumen. It allows for the simulation of different scenarios mimicking the differential transport of chloride, its impact on Ca2+ uptake and release and ultimately on lysosomal homeostasis. We provide a Supplementary Information file (Astaburuaga et al. Cells 2019) with the full description of the mathematical model. The equations written in purple were newly developed, the other elements were retrieved from a previous mathematical model as indicated above.

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