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High lumenal chloride in the lysosome is critical for lysosome function.

ABSTRACT: Lysosomes are organelles responsible for the breakdown and recycling of cellular machinery. Dysfunctional lysosomes give rise to lysosomal storage disorders as well as common neurodegenerative diseases. Here, we use a DNA-based, fluorescent chloride reporter to measure lysosomal chloride in Caenorhabditis elegans as well as murine and human cell culture models of lysosomal diseases. We find that the lysosome is highly enriched in chloride, and that chloride reduction correlates directly with a loss in the degradative function of the lysosome. In nematodes and mammalian cell culture models of diverse lysosomal disorders, where previously only lysosomal pH dysregulation has been described, massive reduction of lumenal chloride is observed that is ~10³ fold greater than the accompanying pH change. Reducing chloride within the lysosome impacts Ca²⁺ release from the lysosome and impedes the activity of specific lysosomal enzymes indicating a broader role for chloride in lysosomal function.

SUBMITTER: Chakraborty K

PROVIDER: S-EPMC5526669 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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High lumenal chloride in the lysosome is critical for lysosome function.

Chakraborty Kasturi K Leung KaHo K Krishnan Yamuna Y

eLife 20170725

Lysosomes are organelles responsible for the breakdown and recycling of cellular machinery. Dysfunctional lysosomes give rise to lysosomal storage disorders as well as common neurodegenerative diseases. Here, we use a DNA-based, fluorescent chloride reporter to measure lysosomal chloride in <i>Caenorhabditis elegans</i> as well as murine and human cell culture models of lysosomal diseases. We find that the lysosome is highly enriched in chloride, and that chloride reduction correlates directly w ...[more]

PMID: 28742019

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Project description:BackgroundThe objective of this systematic review and meta-analysis was to assess the relationship between the chloride content of intravenous resuscitation fluids and patient outcomes in the perioperative or intensive care setting.MethodsSystematic searches were performed of PubMed/MEDLINE, Embase and Cochrane Library (CENTRAL) databases in accordance with PRISMA guidelines. Randomized clinical trials, controlled clinical trials and observational studies were included if they compared outcomes in acutely ill or surgical patients receiving either high-chloride (ion concentration greater than 111?mmol/l up to and including 154?mmol/l) or lower-chloride (concentration 111?mmol/l or less) crystalloids for resuscitation. Endpoints examined were mortality, measures of kidney function, serum chloride, hyperchloraemia/metabolic acidosis, blood transfusion volume, mechanical ventilation time, and length of hospital and intensive care unit stay. Risk ratios (RRs), mean differences (MDs) or standardized mean differences (SMDs) and confidence intervals were calculated using fixed-effect modelling.ResultsThe search identified 21 studies involving 6253 patients. High-chloride fluids did not affect mortality but were associated with a significantly higher risk of acute kidney injury (RR 1.64, 95 per cent c.i. 1.27 to 2.13; P?<?0.001) and hyperchloraemia/metabolic acidosis (RR 2.87, 1.95 to 4.21; P?<?0.001). High-chloride fluids were also associated with greater serum chloride (MD 3.70 (95 per cent c.i. 3.36 to 4.04) mmol/l; P?<?0.001), blood transfusion volume (SMD 0.35, 0.07 to 0.63; P?=?0.014) and mechanical ventilation time (SMD 0.15, 0.08 to 0.23; P?<?0.001). Sensitivity analyses excluding heavily weighted studies resulted in non-statistically significant effects for acute kidney injury and mechanical ventilation time.ConclusionA weak but significant association between higher chloride content fluids and unfavourable outcomes was found, but mortality was unaffected by chloride content.

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High lumenal chloride in the lysosome is critical for lysosome function.

Publications

High lumenal chloride in the lysosome is critical for lysosome function.

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