A Mathematical Model of Lysosomal Ion Homeostasis Points to Differential Effects of Cl− Transport in Ca2+ Dynamics

Abstract

The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in keeping proper ion homeostasis have pathological consequences. Accordingly, several human diseases are caused by the dysfunction of ion transporters. These include osteopetrosis, caused by the dysfunction of Cl−/H+ exchange by the lysosomal transporter ClC-7. To better understand how chloride transport affects lysosomal ion homeostasis and how its disruption impinges on lysosomal function, we developed a mathematical model of lysosomal ion homeostasis including Ca2+ dynamics. The model recapitulates known biophysical properties of ClC-7 and enables the investigation of its differential activation kinetics on lysosomal ion homeostasis. We show that normal functioning of ClC-7 supports the acidification process, is associated with increased luminal concentrations of sodium, potassium, and chloride, and leads to a higher Ca2+ uptake and release. Our model highlights the role of ClC-7 in lysosomal acidification and shows the existence of differential Ca2+ dynamics upon perturbations of Cl−/H+ exchange and its activation kinetics, with possible pathological consequences.

Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters

“…As in in Clcn7 −/− cells, lysosomes were acidified to the normally low pH. As predictable from model calculations (Weinert et al, 2010 ; Ishida et al, 2013 ; Astaburuaga et al, 2019 ), the lysosomal Cl − concentration was reduced in both Clcn7 −/− and Clcn7 unc/unc mice compared to wild-type (Weinert et al, 2010 ). Similar results, reduced [Cl − ] but normally acidic pH, were obtained with nematode models with reduced ClC-7 or Ostm1 orthologs (Chakraborty et al, 2017 ).…”

“…The presence of a Cl − /H + exchanger does not only –if at all– affect the luminal Cl − concentration and pH, but ion homeostasis in general, including the transmembrane voltage and concentrations of other ion species (Ishida et al, 2013 ; Stauber and Jentsch, 2013 ; Astaburuaga et al, 2019 ) ( Figure 3 ). One particularly important ion species that may be affected is Ca 2+ (Chakraborty et al, 2017 ; Astaburuaga et al, 2019 ), as it is crucially involved in signaling and trafficking in the endosomal-lysosomal pathway (Luzio et al, 2007 ; Morgan et al, 2011 ; Ureshino et al, 2019 ; Lakpa et al, 2020 ). In addition, the exchange activity of CLCs has osmotic effects on the respective organelles.…”

“…The cartoon was created using Servier Medical Art templates ( https://smart.servier.com ) licensed under a Creative Commons License ( https://creativecommons.org/licenses/by/3.0/ ). The figure was taken from Astaburuaga et al ( 2019 ).…”

“…In addition to the acidification of early endosomes, a pivotal role of the vesicular CLCs is the pH gradient-dependent secondary active accumulation of luminal Cl − , as highlighted in engineered mouse models in which individual CLC exchangers were mutated to pure chloride conductors (Novarino et al, 2010 ; Weinert et al, 2010 , 2020 ). The importance of lysosomal Cl − is still elusive, but it may affect further parameters of the vesicular ion homeostasis including Ca 2+ (Stauber and Jentsch, 2013 ; Chakraborty et al, 2017 ; Astaburuaga et al, 2019 ).…”

“…As long-living post-mitotic cells, neurons are particularly reliant on a functioning endosomal-lysosomal system because of its function in cellular clearance and stress sensing (Boland et al, 2018 ; Mallucci et al, 2020 ; Nixon, 2020 ). Numerous pumps, transporters and channels also mediate the transport of ions required for the physiological functions of these compartments in the endosomal-lysosomal pathway and their dysfunction often underlies inherited disorders of various kinds (Xu and Ren, 2015 ; Xu et al, 2015 ; Astaburuaga et al, 2019 ; Huizing and Gahl, 2020 ). A key player in the ion homeostasis of endosomes and lysosomes, as well as synaptic vesicles, is the V-ATPase.…”