Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

Abstract

Ca2+ plays a pivotal role in mitochondrial energy production, contraction, and apoptosis. Mitochondrial Ca2+-targeted fluorescent probes have demonstrated that mitochondria Ca2+ transients are synchronized with Ca2+ fluxes occurring in the sarcoplasmic reticulum (SR). The presence of specialized proteins tethering SR to mitochondria ensures the local Ca2+ flux between these organelles. Furthermore, communication between SR and mitochondria impacts their functionality in a bidirectional manner. Mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniplex is essential for ATP production and controlled reactive oxygen species levels for proper cellular signaling. Conversely, mitochondrial ATP ensures the proper functioning of SR Ca2+-handling proteins, which ensures that mitochondria receive an adequate supply of Ca2+. Recent evidence suggests that altered SR Ca2+ proteins, such as ryanodine receptors and the sarco/endoplasmic reticulum Ca2+ ATPase pump, play an important role in maintaining proper cardiac membrane excitability, which may be initiated and potentiated when mitochondria are dysfunctional. This recognized mitochondrial role offers the opportunity to develop new therapeutic approaches aimed at preventing cardiac arrhythmias in cardiac disease.

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“…However, calcium ions, either at lower or above threshold levels in the mitochondrial matrix, influence mitochondrial metabolic fate. Likewise, dysfunctional mitochondria potentiate mitochondrial calcium signaling ( Salazar-Ramírez et al, 2020 ). During mitochondrial calcium overload, profound generation of ROS, increased mitochondrial apoptosis, contraction, and immoderation of mitochondrial membrane potential are observed.…”

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“…The presence of specialized proteins that connect the SR to the mitochondria ensures local calcium flux between these organelles. Recent evidence suggests that acquired modifications of ER-mitochondrial Ca 2+ -handling proteins cause abnormal calcium flow between organelles, and their resulting disturbed calcium balance is associated with arrhythmias ( Salazar-Ramirez et al, 2020 ). The altered SR Ca 2+ handling proteins, such as RyRs and IP3R, play an important role in maintaining appropriate cardiomyocyte excitability, which may be initiated and intensified when mitochondria are dysfunctional ( Salazar-Ramirez et al, 2020 ).…”

“…Recent evidence suggests that acquired modifications of ER-mitochondrial Ca 2+ -handling proteins cause abnormal calcium flow between organelles, and their resulting disturbed calcium balance is associated with arrhythmias ( Salazar-Ramirez et al, 2020 ). The altered SR Ca 2+ handling proteins, such as RyRs and IP3R, play an important role in maintaining appropriate cardiomyocyte excitability, which may be initiated and intensified when mitochondria are dysfunctional ( Salazar-Ramirez et al, 2020 ). Moreover, the junctional sarcoplasmic reticulum (jSR) is an important and specialized ER subdomain that concentrates resident proteins to regulate Ca 2+ release in adult cardiomyocytes ( Sleiman et al, 2015 ), jSR, mitochondria, and transverse-tubules (TTs), which are specialized sarcolemma invaginations, are tightly regulated and form an important and highly repetitive functional structure along the cell ( De la Fuente and Sheu, 2019 ).…”

“…Moreover, the junctional sarcoplasmic reticulum (jSR) is an important and specialized ER subdomain that concentrates resident proteins to regulate Ca 2+ release in adult cardiomyocytes ( Sleiman et al, 2015 ), jSR, mitochondria, and transverse-tubules (TTs), which are specialized sarcolemma invaginations, are tightly regulated and form an important and highly repetitive functional structure along the cell ( De la Fuente and Sheu, 2019 ). Mitochondrial Ca-targeted fluorescent probes have revealed that mitochondria Ca 2+ transients are synchronized with SR Ca 2+ fluxes ( Salazar-Ramirez et al, 2020 ). Different research groups provided evidence indicating that erratic abnormal action potential (AP) generation relies on pathological mitochondria-derived ROS (mdROS), and interaction between mitochondria and the SR ( Salazar-Ramirez et al, 2020 ).…”

“…Mitochondrial Ca-targeted fluorescent probes have revealed that mitochondria Ca 2+ transients are synchronized with SR Ca 2+ fluxes ( Salazar-Ramirez et al, 2020 ). Different research groups provided evidence indicating that erratic abnormal action potential (AP) generation relies on pathological mitochondria-derived ROS (mdROS), and interaction between mitochondria and the SR ( Salazar-Ramirez et al, 2020 ). Li Q. et al (2015) developed a multiscale guinea pig cardiomyocyte model that included the mitochondria-SR microdomain for the first time.…”