Chloride ions in health and disease

Abstract

Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl-, which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles.

Keywords: Anion transport; Chloride channels; Chloride ions; Chloride transporters; Ion homeostasis.

Figure 1. Chloride concentrations in adult human organs

The Cl⁻ concentration in adult human organs varies in different organ systems. The Cl⁻ concentration in the brain (41 mM), heart (overall 45 mM, and specifically right ventricle 339 mM and left ventricle 201 mM), muscle (25 mM), kidney (58 mM), blood (98–106 mM), gut (150 mM), skin (71 mM), liver (38 mM), and lungs (30 mM). Associated human diseases for various organs are highlighted. All the values were obtained from previous studies [26–28,31,36,40,50,81–83,88,116,156,157,169,195–206]. Images were generated by Biorender.

Figure 2. Schematic representation of chloride concentration in the cell organelles

The Cl⁻ concentration in an extracellular and cellular compartment maintains cellular homeostasis. The extracellular Cl⁻ concentration (110 mM), cytosol (36 mM), early endosome (40 mM), late endosome (65 mM), lysosome (118 mM), mitochondria (0.9–22.2 mM), nucleus (35–85 mM), endoplasmic reticulum (3 mM), and Golgi apparatus (50 mM) [83,133,134,169,175,192,207,208].