Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

Abstract Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic spines. This exquisite level of Ca2+ compartmentalization is achieved through the storage and release of Ca2+ from various intracellular organelles particularly the endoplasmi...

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Autores principales:	A. Leung, D. Ohadi, G. Pekkurnaz, P. Rangamani
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e27fbe6a215243f5a00836af385ac281
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spelling	oai:doaj.org-article:e27fbe6a215243f5a00836af385ac2812021-12-02T18:25:06ZSystems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape10.1038/s41540-021-00185-72056-7189https://doaj.org/article/e27fbe6a215243f5a00836af385ac2812021-06-01T00:00:00Zhttps://doi.org/10.1038/s41540-021-00185-7https://doaj.org/toc/2056-7189Abstract Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic 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 (MERCs), 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 inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal 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.A. LeungD. OhadiG. PekkurnazP. RangamaniNature PortfolioarticleBiology (General)QH301-705.5ENnpj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 A. Leung D. Ohadi G. Pekkurnaz P. Rangamani Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape
description	Abstract Spatiotemporal compartmentation of calcium dynamics is critical for neuronal function, particularly in postsynaptic 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 (MERCs), 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 inter-organellar contact sites play a key role in modulating Ca2+ and ATP dynamics. We further show that the crosstalk between geometry (mitochondria and MERC) and metabolic parameters (cytosolic ATP hydrolysis, ATP generation) influences the neuronal 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.
format	article
author	A. Leung D. Ohadi G. Pekkurnaz P. Rangamani
author_facet	A. Leung D. Ohadi G. Pekkurnaz P. Rangamani
author_sort	A. Leung
title	Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape
title_short	Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape
title_full	Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape
title_fullStr	Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape
title_full_unstemmed	Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape
title_sort	systems modeling predicts that mitochondria er contact sites regulate the postsynaptic energy landscape
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e27fbe6a215243f5a00836af385ac281
work_keys_str_mv	AT aleung systemsmodelingpredictsthatmitochondriaercontactsitesregulatethepostsynapticenergylandscape AT dohadi systemsmodelingpredictsthatmitochondriaercontactsitesregulatethepostsynapticenergylandscape AT gpekkurnaz systemsmodelingpredictsthatmitochondriaercontactsitesregulatethepostsynapticenergylandscape AT prangamani systemsmodelingpredictsthatmitochondriaercontactsitesregulatethepostsynapticenergylandscape
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Systems modeling predicts that mitochondria ER contact sites regulate the postsynaptic energy landscape

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