Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model.
Mitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca2+) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca2+ alternans in cardiac myocytes has been observed in experiments...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1008624 |
| _version_ | 1811181737317761024 |
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| author | Vikas Pandey Lai-Hua Xie Zhilin Qu Zhen Song |
| author_facet | Vikas Pandey Lai-Hua Xie Zhilin Qu Zhen Song |
| author_sort | Vikas Pandey |
| collection | DOAJ |
| description | Mitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca2+) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca2+ alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca2+ cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca2+ alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca2+ cycling and complex signaling pathways to investigate the mechanisms of Ca2+ alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca2+ alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Ca2+-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca2+ uniporter promotes Ca2+ alternans via Ca2+-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca2+/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca2+ alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco/endoplasmic reticulum Ca2+-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca2+ alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca2+ alternans chronically through oxidized Ca2+/calmodulin-dependent protein kinase II activation. |
| first_indexed | 2024-04-11T09:22:31Z |
| format | Article |
| id | doaj.art-5cbaad014ff44f198244606c3b9e38e4 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-11T09:22:31Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-5cbaad014ff44f198244606c3b9e38e42022-12-22T04:32:09ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582021-01-01171e100862410.1371/journal.pcbi.1008624Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model.Vikas PandeyLai-Hua XieZhilin QuZhen SongMitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca2+) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca2+ alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca2+ cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca2+ alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca2+ cycling and complex signaling pathways to investigate the mechanisms of Ca2+ alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca2+ alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Ca2+-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca2+ uniporter promotes Ca2+ alternans via Ca2+-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca2+/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca2+ alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco/endoplasmic reticulum Ca2+-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca2+ alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca2+ alternans chronically through oxidized Ca2+/calmodulin-dependent protein kinase II activation.https://doi.org/10.1371/journal.pcbi.1008624 |
| spellingShingle | Vikas Pandey Lai-Hua Xie Zhilin Qu Zhen Song Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model. PLoS Computational Biology |
| title | Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model. |
| title_full | Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model. |
| title_fullStr | Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model. |
| title_full_unstemmed | Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model. |
| title_short | Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model. |
| title_sort | mitochondrial depolarization promotes calcium alternans mechanistic insights from a ventricular myocyte model |
| url | https://doi.org/10.1371/journal.pcbi.1008624 |
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