On the Electrophysiological Component of Pancreatic Alpha-Cell Models.

Glucagon, the main hormone responsible for increasing blood glucose levels, is secreted by pancreatic alphacells in a Ca2+ dependent process associated to membrane potential oscillations developed by the dynamic operation of K+, Na+ and Ca2+ channels. The mechanisms behind membrane potential and Ca2+ oscillations in alpha-cells are still under debate, and some new research works have used alpha-cell models to describe electrical activity. In this paper we studied the dynamics of electrical activity of three alpha-cell models using the Lead Potential Analysis method and Bifurcation Diagrams. Our aim is to highlight the differences in their dynamic behavior and therefore, in their response to glucose. Both issues are relevant to understand the stimulus-secretion coupling in alpha-cells and then, the mechanisms behind their dysregulation in Type 2 Diabetes.Clinical Relevance - A reliable description of the electrophysiological mechanisms in pancreatic alpha-cells is key to understand and treat the dysregulation of these cells in patients with Type 2 Diabetes.

Reduction of ER-Mitochondria Distance: a Key Feature in Alzheimer's and Parkinson's Disease, and During Cancer Treatment.

One remarkable dynamic cell structure is the region between the endoplasmic reticulum (ER) and the mitochondria, termed the mitochondria-associated membranes (MAM). MAMs carry out different cellular functions such as Ca2+ homeostasis and lipid synthesis, which depend on an adequate distance separating the ER and mitochondria. A decreased distance has been observed in Alzheimer's disease, Parkinson's disease, and during cancer treatment. It is unclear how dysregulation of the spatial characteristics of MAMs can cause abnormal Ca2+ dynamics which could end in cell death. In this work, a computational model was proposed to study the relationship between a decreased ER-mitochondria distance and mitochondria-induced cell death. Our results point towards the mitochondrial permeability transition pore (mPTP) as a key cell death signaling mechanism indirectly regulated by the spatial characteristics of MAMs.Clinical Relevance- The endoplasmic reticulum-mitochondria crosstalk plays an important role in the mPTP-induced apoptosis. This process could be behind neurodegeneration in Alzheimer's and Parkinson's diseases, as well as behind the induced cell death during cancer treatment.

Mitochondrial Ca2+ dynamics in cells and suspensions.

Mitochondria play a significant role in shaping cytosolic Ca2+ signals. Thus, transfer of Ca2+ across the mitochondrial membrane is much studied, not only in intact cells but also in artificial systems such as mitochondrial suspensions or permeabilised cells. Observed rates of Ca2+ changes vary by at least one order of magnitude. In this work, we investigate the relationship between the Ca2+ dynamics observed in various experimental conditions using a computational model calibrated on experimental data. Results confirm that mitochondrial Ca2+ exchange fluxes through the mitochondrial Ca2+ uniporter (MCU) and the Na+ /Ca2+ exchanger obey the same basic kinetics in cells and in suspensions, and emphasise the important role played by the high Ca2+ levels reached in mitochondria-associated endoplasmic reticulum membranes in intact cells. Tissue specificity can be ascribed to the different modes of regulation of the MCU by Ca2+ , probably related to the specific levels of expression of the Ca2+ sensing regulator subunit of this channel. The model emphasises the importance of mitochondrial density and buffering in controlling the rate of Ca2+ exchanges with mitochondria, as verified experimentally. Finally, we show that heterogeneity between individual mitochondria can explain the large range of amplitudes and rates of rise in mitochondrial Ca2+ concentration that have been observed experimentally.