Investigation into the difference in mitochondrial-cytosolic calcium coupling between adult cardiomyocyte and hiPSC-CM using a novel multifunctional genetic probe
Abstract $ Ca^{2+} $ cycling plays a critical role in regulating cardiomyocyte (CM) function under both physiological and pathological conditions. Mitochondria have been implicated in $ Ca^{2+} $ handling in adult cardiomyocytes (ACMs). However, little is known about their role in the regulation of $ Ca^{2+} $ dynamics in human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). In the present study, we developed a multifunctional genetically encoded $ Ca^{2+} $ probe capable of simultaneously measuring cytosolic and mitochondrial $ Ca^{2+} $ in real time. Using this novel probe, we determined and compared mitochondrial $ Ca^{2+} $ activity and the coupling with cytosolic $ Ca^{2+} $ dynamics in hiPSC-CMs and ACMs. Our data showed that while ACMs displayed a highly coordinated beat-by-beat response in mitochondrial $ Ca^{2+} $ in sync with cytosolic $ Ca^{2+} $, hiPSC-CMs showed high cell-wide variability in mitochondrial $ Ca^{2+} $ activity that is poorly coordinated with cytosolic $ Ca^{2+} $. We then revealed that mitochondrial-sarcoplasmic reticulum (SR) tethering, as well as the inter-mitochondrial network connection, is underdeveloped in hiPSC-CM compared to ACM, which may underlie the observed spatiotemporal decoupling between cytosolic and mitochondrial $ Ca^{2+} $ dynamics. Finally, we showed that knockdown of mitofusin-2 (Mfn2), a protein tethering mitochondria and SR, led to reduced cytosolic-mitochondrial $ Ca^{2+} $ coupling in ACMs, albeit to a lesser degree compared to hiPSC-CMs, suggesting that Mfn2 is a potential engineering target for improving mitochondrial-cytosolic $ Ca^{2+} $ coupling in hiPSC-CMs. Physiological relevance: The present study will advance our understanding of the role of mitochondria in $ Ca^{2+} $ handling and cycling in CMs, and guide the development of hiPSC-CMs for healing injured hearts..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:473 |
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| Enthalten in: |
Pflügers Archiv - 473(2021), 3 vom: 15. Feb., Seite 447-459 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ernst, Patrick [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Ca |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021 |
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| doi: |
10.1007/s00424-021-02524-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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OLC2124221418 |
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| 520 | |a Abstract $ Ca^{2+} $ cycling plays a critical role in regulating cardiomyocyte (CM) function under both physiological and pathological conditions. Mitochondria have been implicated in $ Ca^{2+} $ handling in adult cardiomyocytes (ACMs). However, little is known about their role in the regulation of $ Ca^{2+} $ dynamics in human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). In the present study, we developed a multifunctional genetically encoded $ Ca^{2+} $ probe capable of simultaneously measuring cytosolic and mitochondrial $ Ca^{2+} $ in real time. Using this novel probe, we determined and compared mitochondrial $ Ca^{2+} $ activity and the coupling with cytosolic $ Ca^{2+} $ dynamics in hiPSC-CMs and ACMs. Our data showed that while ACMs displayed a highly coordinated beat-by-beat response in mitochondrial $ Ca^{2+} $ in sync with cytosolic $ Ca^{2+} $, hiPSC-CMs showed high cell-wide variability in mitochondrial $ Ca^{2+} $ activity that is poorly coordinated with cytosolic $ Ca^{2+} $. We then revealed that mitochondrial-sarcoplasmic reticulum (SR) tethering, as well as the inter-mitochondrial network connection, is underdeveloped in hiPSC-CM compared to ACM, which may underlie the observed spatiotemporal decoupling between cytosolic and mitochondrial $ Ca^{2+} $ dynamics. Finally, we showed that knockdown of mitofusin-2 (Mfn2), a protein tethering mitochondria and SR, led to reduced cytosolic-mitochondrial $ Ca^{2+} $ coupling in ACMs, albeit to a lesser degree compared to hiPSC-CMs, suggesting that Mfn2 is a potential engineering target for improving mitochondrial-cytosolic $ Ca^{2+} $ coupling in hiPSC-CMs. Physiological relevance: The present study will advance our understanding of the role of mitochondria in $ Ca^{2+} $ handling and cycling in CMs, and guide the development of hiPSC-CMs for healing injured hearts. | ||
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| 700 | 1 | |a Chen, Kai |4 aut | |
| 700 | 1 | |a Tang, Yawen |4 aut | |
| 700 | 1 | |a Kim, Seulhee |4 aut | |
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| 700 | 1 | |a He, Jin |4 aut | |
| 700 | 1 | |a Xie, Min |4 aut | |
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| 700 | 1 | |a Liu, Xiaoguang Margaret |4 aut | |
| 700 | 1 | |a Zhou, Lufang |0 (orcid)0000-0002-1321-8442 |4 aut | |
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