A computational model of lysosome-ER Ca2+ microdomains

Area of Science:

• Cellular Biology
• Biophysics
• Computational Biology

Background:

• Acidic organelles, particularly lysosomes, represent a significant intracellular calcium (Ca2+) pool.
• Lysosomes can influence global Ca2+ signals by coupling with endoplasmic reticulum (ER) Ca2+ stores.
• Lysosome-ER membrane contact sites are recently identified structures potentially involved in Ca2+ dynamics.

Purpose of the Study:

• To develop a computational model of lysosome-ER coupling to investigate Ca2+ dynamics.
• To explore the role of lysosomal leaks and ER Ca2+ channels in generating Ca2+ signals.
• To assess the capability of lysosome-ER microdomains in driving global Ca2+ oscillations.

Main Methods:

• Generation of a computational model integrating lysosomal leaks and inositol trisphosphate (IP3) receptor dynamics.
• Simulation of Ca2+ responses to lysosomotropic agents like GPN.
• Adaptation of the model for physiological Ca2+ mobilization by NAADP.

Main Results:

• The model qualitatively reproduced global Ca2+ responses to lysosomal solute depletion.
• Simulations indicated that lysosome-ER microdomains can drive global Ca2+ oscillations.
• Microdomain Ca2+ concentration did not necessarily need to exceed cytosolic levels for responses, consistent with IP3 receptor affinity.
• Lysosomal leak distribution and density determined whether microdomains triggered or modulated Ca2+ signals.

Conclusions:

• Lysosome-ER microdomains are functionally significant for regulating global Ca2+ dynamics.
• Computational modeling provides a framework for studying lysosome-ER Ca2+ signaling.
• The interplay between lysosomal leaks and ER Ca2+ channels is crucial for cellular Ca2+ homeostasis.