title: The low conductance mitochondrial permeability transition pore confers excitability and CICR wave propagation in a computational model.
abstract: Mitochondria have long been known to sequester cytosolic Ca(2+) and even to shape intracellular patterns of endoplasmic reticulum-based Ca(2+) signaling. Evidence suggests that the mitochondrial network is an excitable medium which can demonstrate independent Ca(2+) induced Ca(2+) release via the mitochondrial permeability transition. The role of this excitability remains unclear, but mitochondrial Ca(2+) handling appears to be a crucial element in diverse diseases as diabetes, neurodegeneration and cardiac dysfunction that also have bioenergetic components. In this paper, we extend the modular Magnus-Keizer computational model for respiration-driven Ca(2+) handling to include a permeability transition based on a channel-like pore mechanism. We demonstrate both excitability and Ca(2+) wave propagation accompanied by depolarizations qualitatively similar to those reported in cell and isolated mitochondria preparations. These waves depend on the energy state of the mitochondria, as well as other elements of mitochondrial physiology. Our results support the concept that mitochondria can transmit state dependent signals about their function across the mitochondrial network. Our model provides the tools for predictions about the internal physiology that leads to this qualitatively different Ca(2+) excitability seen in mitochondria.
authors.affiliation: Group for Neural Theory, Département d'Études Cognitives, École Normale Supérieure, Paris, France.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Oster
authors.forename: Balbir
authors.initials: B
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Terman
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Fall
mesh_terms: D002021:Buffers; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D003198:Computer Simulation; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological; D011522:Protons; D013997:Time Factors
chemical_list: D002021:Buffers; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011522:Protons; D005947:Glucose; D002118:Calcium