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Investigation into the difference in mitochondrial-cytosolic calcium coupling between adult cardiomyocyte and hiPSC-CM using a novel multifunctional genetic probe

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Abstract

Ca2+ cycling plays a critical role in regulating cardiomyocyte (CM) function under both physiological and pathological conditions. Mitochondria have been implicated in Ca2+ handling in adult cardiomyocytes (ACMs). However, little is known about their role in the regulation of Ca2+ dynamics in human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). In the present study, we developed a multifunctional genetically encoded Ca2+ probe capable of simultaneously measuring cytosolic and mitochondrial Ca2+ in real time. Using this novel probe, we determined and compared mitochondrial Ca2+ activity and the coupling with cytosolic Ca2+ dynamics in hiPSC-CMs and ACMs. Our data showed that while ACMs displayed a highly coordinated beat-by-beat response in mitochondrial Ca2+ in sync with cytosolic Ca2+, hiPSC-CMs showed high cell-wide variability in mitochondrial Ca2+ activity that is poorly coordinated with cytosolic Ca2+. 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 Ca2+ dynamics. Finally, we showed that knockdown of mitofusin-2 (Mfn2), a protein tethering mitochondria and SR, led to reduced cytosolic-mitochondrial Ca2+ coupling in ACMs, albeit to a lesser degree compared to hiPSC-CMs, suggesting that Mfn2 is a potential engineering target for improving mitochondrial-cytosolic Ca2+ coupling in hiPSC-CMs. Physiological relevance: The present study will advance our understanding of the role of mitochondria in Ca2+ handling and cycling in CMs, and guide the development of hiPSC-CMs for healing injured hearts.

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Funding

This work is supported by the National Institutes of Health (R01s HL121206 and HL128044 to LZ) and American Heart Association Predoctoral Fellowship (18PRE34060188 to PE).

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Authors and Affiliations

  1. Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Patrick Ernst, Kai Chen, Seulhee Kim, Jiashiung Guan, Jin He, Min Xie & Lufang Zhou

  2. Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Patrick Ernst, Yawen Tang, Jianyi Jay Zhang, Xiaoguang Margaret Liu & Lufang Zhou

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  1. Patrick Ernst
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Contributions

PE, KS, and JG performed experiments and analyzed data. KC, JH and MX and YT and JJZ contributed to the adult mouse CM isolation, NRVM isolation, and iPSC-CM differentiation, respectively. PE, XL, and LZ designed the study. PE, XL, and LZ prepared the manuscript.

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Correspondence to Lufang Zhou.

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This article is part of the special issue on Calcium Signal Dynamics in Cardiac Myocytes and Fibroblasts: Mechanisms in Pflügers Archiv—European Journal of Physiology

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Ernst, P., Chen, K., Tang, Y. et al. Investigation into the difference in mitochondrial-cytosolic calcium coupling between adult cardiomyocyte and hiPSC-CM using a novel multifunctional genetic probe. Pflugers Arch - Eur J Physiol 473, 447–459 (2021). https://doi.org/10.1007/s00424-021-02524-3

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