Goncalves, I. G. | bioRxiv Science

bioRxiv2022

PhysiCOOL: A generalized framework for model Calibration and Optimization Of modeLing projects

In silico models of biological systems are usually very complex and rely on several parameters describing physical and biological properties that require validation. As such, parameter space exploration is an essential component of computational model development to fully characterize and validate simulation results. Experimental data may also be used to constrain parameter space (or enable model calibration) to enhance the biological relevance of model parameters. One widely used computational platform in the mathematical biology community is PhysiCell which provides a standardized approach to agent-based models of biological phenomena at different time and spatial scales. Nonetheless, one limitation of PhysiCell is that there has not been a generalized approach for parameter space exploration and calibration that can be run without high-performance computing access. Taking this into account, we present PhysiCOOL, an open-source Python library tailored to create standardized calibration and optimization routines of PhysiCell models. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/516671v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@16d2601org.highwire.dtl.DTLVardef@da335dorg.highwire.dtl.DTLVardef@1623bd3org.highwire.dtl.DTLVardef@45d9f4_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2019

Mitochondrial Morphology Regulates Organellar Ca2+ Uptake and Changes Cellular Ca2+ Homeostasis

Changes in mitochondrial size and shape have been implicated in several physiological processes, but their role in mitochondrial Ca2+ uptake regulation and overall cellular Ca2+ homeostasis is largely unknown. Here we show that modulating mitochondrial dynamics towards increased fusion through expression of a dominant negative form of the fission protein DRP1 (DRP1-DN) markedly increased both mitochondrial Ca2+ retention capacity and Ca2+ uptake rates in permeabilized C2C12 cells. Similar results were seen using the pharmacological fusion-promoting M1 molecule. Conversely, promoting a fission phenotype through the knockdown of the fusion protein mitofusin 2 (MFN2) strongly reduced mitochondrial Ca2+ uptake speed and capacity in these cells. These changes were not dependent on modifications in inner membrane potentials or the mitochondrial permeability transition. Implications of mitochondrial morphology modulation on cellular calcium homeostasis were measured in intact cells; mitochondrial fission promoted lower basal cellular calcium levels and lower endoplasmic reticulum (ER) calcium stores, as measured by depletion with thapsigargin. Indeed, mitochondrial fission was associated with ER stress. Additionally, the calcium-replenishing process of store-operated calcium entry (SOCE) was impaired in MFN2 knockdown cells, while DRP1-DN-promoted fusion resulted in faster cytosolic Ca2+ increase rates. Overall, our results show a novel role for mitochondrial morphology in the regulation of mitochondrial Ca2+ uptake, which impacts on cellular Ca2+ homeostasis.

cell biology↗