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ABSTRACT Human induced pluripotent stem cell‐derived cardiomyocytes are valuable for studying cell–cell communication and synchronization, but remain immature and often lack robust electrical and mechanical coupling. To address this, we investigated gap junction‐mediated communication and developed plasma membrane vesicles enriched in functional connexin hemichannels, termed Connectosomes, to enhance intercellular coupling. Connectosomes display properly oriented connexins and enrich the Cx43 expression at cell–cell borders between cardiomyocytes. Through mathematical modeling and experimental validation, we demonstrate that Connectosome incorporation reinforces endogenous gap junctions, promotes synchronous calcium transients, and improves spatial coordination of beating across networks. Mechanistic studies using engineered cell lines with tagged connexin‐43 confirm that channel orientation and functionality are critical, supporting a model in which Connectosomes contribute to gap junction coupling. These results show that Connectosomes can synchronize the beating of immature cardiomyocytes by boosting electrochemical communication, laying the groundwork for future therapeutic advances.
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Mitochondrial Connexins and Mitochondrial Contact Sites with Gap Junction Structure
Mitochondria contain connexins, a family of proteins that is known to form gap junction channels. Connexins are synthesized in the endoplasmic reticulum and oligomerized in the Golgi to form hemichannels. Hemichannels from adjacent cells dock with one another to form gap junction channels that aggregate into plaques and allow cell–cell communication. Cell–cell communication was once thought to be the only function of connexins and their gap junction channels. In the mitochondria, however, connexins have been identified as monomers and assembled into hemichannels, thus questioning their role solely as cell–cell communication channels. Accordingly, mitochondrial connexins have been suggested to play critical roles in the regulation of mitochondrial functions, including potassium fluxes and respiration. However, while much is known about plasma membrane gap junction channel connexins, the presence and function of mitochondrial connexins remain poorly understood. In this review, the presence and role of mitochondrial connexins and mitochondrial/connexin-containing structure contact sites will be discussed. An understanding of the significance of mitochondrial connexins and their connexin contact sites is essential to our knowledge of connexins’ functions in normal and pathological conditions, and this information may aid in the development of therapeutic interventions in diseases linked to mitochondria.
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- PAR ID:
- 10503764
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- International Journal of Molecular Sciences
- Volume:
- 24
- Issue:
- 10
- ISSN:
- 1422-0067
- Page Range / eLocation ID:
- 9036
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.3390/ijms24109036
