Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Mohit M Hulsurkar1,2, Satadru K Lahiri1,2, Jason Karch1,2
1Baylor College of Medicine, Houston TX USA.
Insights
Dysregulated calcium signaling between the sarcoplasmic reticulum, mitochondria, and lysosomes is implicated in heart disease. Targeting these calcium channels offers potential therapeutic strategies for cardiac conditions.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
- Molecular Cardiology
Background:
- Abnormal calcium signaling between organelles is a hallmark of heart diseases.
- Calcium acts as a crucial secondary messenger in cardiomyocyte function and inter-organellar communication.
Purpose of the Study:
- To review literature on calcium channels and transporters in inter-organellar signaling.
- To highlight the dysregulation of this signaling in cardiac pathologies.
Main Methods:
- Literature review of calcium channels and transporters.
- Examination of sarcoplasmic reticulum (SR), mitochondria, and lysosome calcium dynamics.
- Analysis of studies on SR, mitochondria, and lysosome crosstalk in cardiac disease.
Main Results:
- Key channels discussed include RyR2, IP3R, SERCA2a, VDAC, MCUC, TPC, and TRPML.
- Aberrant calcium handling, including enhanced release and reduced reuptake, contributes to heart disease.
- Dysregulated crosstalk between SR, mitochondria, and lysosomes disrupts calcium homeostasis.
Conclusions:
- Interventions targeting specific calcium channels or combinations may offer therapeutic benefits.
- Further research into the mechanisms of inter-organellar calcium crosstalk is warranted.
- Restoring calcium homeostasis through targeted therapies holds promise for treating heart disease.
Introduction:
Abnormal calcium signaling between organelles such as the sarcoplasmic reticulum (SR), mitochondria and lysosomes is a key feature of heart diseases. Calcium serves as a secondary messenger mediating inter-organellar crosstalk, essential for maintaining the cardiomyocyte function.
Areas Covered:
This article examines the available literature related to calcium channels and transporters involved in inter-organellar calcium signaling. The SR calcium-release channels ryanodine receptor type-2 (RyR2) and inositol 1,4,5-trisphosphate receptor (IP3R), and calcium-transporter SR/ER-ATPase 2a (SERCA2a) are illuminated. The roles of mitochondrial voltage-dependent anion channels (VDAC), the mitochondria Ca2+ uniporter complex (MCUC), and the lysosomal H+/Ca2+ exchanger, two pore channels (TPC), and transient receptor potential mucolipin (TRPML) are discussed. Furthermore, recent studies showing calcium-mediated crosstalk between the SR, mitochondria, and lysosomes as well as how this crosstalk is dysregulated in cardiac diseases are placed under the spotlight.
Expert Opinion:
Enhanced SR calcium release via RyR2 and reduced SR reuptake via SERCA2a, increased VDAC and MCUC-mediated calcium uptake into mitochondria, and enhanced lysosomal calcium-release via lysosomal TPC and TRPML may all contribute to aberrant calcium homeostasis causing heart disease. While mechanisms of this crosstalk need to be studied further, interventions targeting these calcium channels or combinations thereof might represent a promising therapeutic strategy.
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