Related Experiment Videos
Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart
Ashish Kumar Gadicherla1, Nan Wang1, Marco Bulic2
1Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185 (Block B, Rm 031), 9000, Ghent, Belgium.
Insights
Mitochondrial connexin 43 (Cx43) hemichannels facilitate calcium entry, potentially causing cell death. The peptide RRNYRRNY inhibits these Cx43 hemichannels, reducing cardiac injury and cell death.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Physiology
- Cell Signaling
Background:
- Mitochondrial connexin 43 (Cx43) is crucial for cardiac protection during ischemic preconditioning.
- Cx43 hemichannels allow calcium (Ca2+) influx, potentially leading to mitochondrial overload and cell death.
Purpose of the Study:
- To investigate the role of Cx43 in mitochondrial Ca2+ entry.
- To explore the downstream effects of Cx43-mediated Ca2+ influx on cell injury.
- To evaluate the therapeutic potential of Cx43-targeting peptides.
Main Methods:
- Utilized connexin-targeting peptides (Gap26, Gap19, RRNYRRNY) to modulate Cx43 activity.
- Assessed mitochondrial Ca2+ uptake, dye uptake, and electrophysiological properties of Cx43 channels.
- Evaluated cell injury and death in isolated mitochondria and ex vivo cardiac models.
Main Results:
- Cx43 forms hemichannels contributing to mitochondrial Ca2+ entry, potentially triggering cell injury and death.
- The peptide RRNYRRNY effectively inhibited both plasma membrane and mitochondrial Cx43 hemichannels.
- RRNYRRNY significantly reduced infarct size in ex vivo cardiac ischemia-reperfusion studies.
Conclusions:
- Cx43 plays a significant role in mitochondrial Ca2+ homeostasis and cell death pathways.
- Targeting Cx43 hemichannels with peptides like RRNYRRNY offers a potential therapeutic strategy for cardiac protection.
Abstract:
Mitochondrial connexin 43 (Cx43) plays a key role in cardiac cytoprotection caused by repeated exposure to short periods of non-lethal ischemia/reperfusion, a condition known as ischemic preconditioning. Cx43 also forms calcium (Ca2+)-permeable hemichannels that may potentially lead to mitochondrial Ca2+ overload and cell death. Here, we studied the role of Cx43 in facilitating mitochondrial Ca2+ entry and investigated its downstream consequences. To that purpose, we used various connexin-targeting peptides interacting with extracellular (Gap26) and intracellular (Gap19, RRNYRRNY) Cx43 domains, and tested their effect on mitochondrial dye- and Ca2+-uptake, electrophysiological properties of plasmalemmal and mitochondrial Cx43 channels, and cell injury/cell death. Our results in isolated mice cardiac subsarcolemmal mitochondria indicate that Cx43 forms hemichannels that contribute to Ca2+ entry and may trigger permeability transition and cell injury/death. RRNYRRNY displayed the strongest effects in all assays and inhibited plasma membrane as well as mitochondrial Cx43 hemichannels. RRNYRRNY also strongly reduced the infarct size in ex vivo cardiac ischemia-reperfusion studies. These results indicate that Cx43 contributes to mitochondrial Ca2+ homeostasis and is involved in triggering cell injury/death pathways that can be inhibited by RRNYRRNY peptide.