RT Journal Article
SR Electronic
T1 Deciphering the postsynaptic calcium-mediated energy homeostasis through mitochondria-endoplasmic reticulum contact sites using systems modeling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.12.294827
DO 10.1101/2020.09.12.294827
A1 A. Leung
A1 D. Ohadi
A1 G. Pekkurnaz
A1 P. Rangamani
YR 2020
UL http://biorxiv.org/content/early/2020/09/13/2020.09.12.294827.abstract
AB Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in post-synaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmic reticulum (ER) and the mitochondria. Mitochondria and ER are established storage organelles controlling Ca2+ dynamics in neurons. Mitochondria also generate a majority of energy used within postsynaptic spines to support the downstream events associated with neuronal stimulus. Recently, high resolution microscopy has unveiled direct contact sites between the ER and the mitochondria, which directly channel Ca2+ release from the ER into the mitochondrial membrane. In this study, we develop a computational 3D reaction-diffusion model to investigate the role of MERCs in regulating Ca2+ and ATP dynamics. This spatiotemporal model accounts for Ca2+ oscillations initiated by glutamate stimulus of metabotropic and ionotropic glutamate receptors and Ca2+ changes in four different compartments: cytosol, ER, mitochondria, and the MERC microdomain. Our simulations predict that the organization of these organelles and differential distribution of key Ca2+ channels such as IP3 receptor and ryanodine receptor modulate Ca2+ dynamics in response to different stimuli. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the cellular energy state. Our findings shed light on the importance of organelle interactions in predicting Ca2+ dynamics in synaptic signaling. Overall, our model predicts that a combination of MERC linkage and mitochondria size is necessary for optimal ATP production in the cytosol.Competing Interest StatementThe authors have declared no competing interest.(ER)Endoplasmic reticulum(IP3)Inositol 1,4,5-trisphosphate(MERC, also MAM)Mitochondrial Endoplamic Reticulum Contact(IP3R)IP3 receptor(RyR)Ryanodine receptor(SERCA)sarcoplasmic/endoplasmic reticulum calcium ATPase(ATP)Adenine triphosphate(OMM)outer mitochondrial membrane(IMS)intermembrane space(MCU)Mitochondrial Calcium Uniporter(PMCA)Plasma Membrane Calcium ATPase(IMM)inner mitochondrial membrane(ETC)Electron Transport Chain(AGC)Aspartate/glutamate carrier(MAS)Malate/asparate shuttle(ANT)Adenine nucleotide translocator(PDH)Pyruvate dehydrogenase(GPDH)Glyceraldehyde 3-phosphate dehydrogenase(NCX)Na+/Ca2+ exchanger(mGluR)Metabotropic glutamate receptor(NMDAR)N-Methyl d-Aspartate Receptor(PKC)Protein kinase C(DAG)Diacyl-glycerol(PSD)Post synaptic density(PIP2)Phosphatidylinositol (4,5)-bisphosphate