Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases

ABSTRACT

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.

KEYWORDS:

• Calcium
• organelle
• Cardiac Diseases
• sarcoplasmic reticulum (SR)
• mitochondria
• lysosomes
• ryanodine receptor

Article highlights

• Sarcoplasmic reticulum (SR), mitochondria and lysosomes are localized in close proximity of each other and communicate with each other through secondary messengers or direct physical contact.

• Calcium (Ca²⁺) is a key secondary messenger mediating the inter-organellar crosstalk, which is essential for coordinating the activities of various organelles and maintaining the overall function of cardiomyocytes.

• SR protein ryanodine receptor type-2 (RyR2) is not only essential for excitation-contraction coupling in cardiomyocytes, but along with Inositol 1,4,5-trisphosphate receptor (IP₃R) plays a key role in releasing Ca²⁺ to mitochondria and lysosomes. Using RyR2 and IP₃R inhibitors could limit the pathological Ca²⁺ release from the SR.

• Mitochondrial proteins voltage dependent anion channels (VDAC) and the mitochondria Ca²⁺ uniporter complex (MCUC) as well as lysosomal H⁺/Ca²⁺ exchanger are essential in uptake of Ca²⁺ and inhibiting these protein complexes could prevent pathological Ca²⁺ overload in mitochondria and lysosomes.

• Pathological Ca²⁺ release from the lysosomes via the Two Pore Channels (TPC) and Transient Receptor Potential Mucolipin (TRPML) channels leads to Ca²⁺-induced Ca²⁺ release (CICR) RyR2, which may lead to Ca²⁺ overload, arrhythmias, cardiomyopathy and eventually heart failure.

• Blocking pathological inter-organellar Ca2+ crosstalk by targeting the aforementioned channels separately or simultaneously could be an effective strategy to treat different cardiovascular diseases.

Declaration of interest

XHT Wehrens is a founding partner of Elex Biotech, a start-up company that developed drug molecules that target RyRs for the treatment of cardiac arrhythmia disorders.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors are supported by National Institutes of Health grants R01HL147188, R01HL153358, and R01HL089598 (to X.H.T.W.), R01HL150031 (to J.K.), R01AG045183, R01AT009050, R01AG062257, P01AG066606, and DP1DK113644 (M.C.W.), and by the Welch Foundation (M.C.W.). M.C.W. is a Howard Hughes Medical Institute Investigator.