Abstract
Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs.
Highlights
Alterations in lysosomal structure and function can lead to complex, pathophysiological manifestations in living organisms [1, 2]
As elaborated in the following subsections, the effects of the aforementioned lysosomal stressors on lysosomal physiology were considered in the context of 1) biologicallydetermined variations in lysosomal morphology, 2) drug induced changes in lysosomal volume and surface area, 3) changes in lysosomal volume and surface area as may happen during endocytosis or exocytosis
We observed a similar physiological perturbation following the modeling of the effect of increasing the lysosomal membrane proton permeability on lysosomal ion homeostasis (Fig 2B)
Summary
Alterations in lysosomal structure and function can lead to complex, pathophysiological manifestations in living organisms [1, 2]. Drug-induced lysosomal stress and resistance of Bristol Myers-Squibb. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Mutations in CLC7 cause osteoporosis and neurodegeneration in mice, and are associated with similar phenotypic effects in humans [11,12,13]. Mutations in TRPML are associated with an autosomal-recessive lysosomal storage disease known as MLIV [14,15,16], whereas mutations in V-ATPase are associated with osteoporosis, renal tubular acidosis, and deafness in humans, and cause similar effects in mice [17,18,19,20]. Perturbations in vesicular trafficking which affect ion transport functions can adversely affect cellular function which leads to muscle degeneration [21]
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