Sarcoplasmic Reticulum-Mitochondria Kissing in Cardiomyocytes: Ca2+, ATP, and Undisclosed Secrets

Abstract

In cardiomyocytes, to carry out cell contraction, the distribution, morphology, and dynamic interaction of different cellular organelles are tightly regulated. For instance, the repetitive close apposition between junctional sarcoplasmic reticulum (jSR) and specialized sarcolemma invaginations, called transverse-tubules (TTs), is essential for an efficient excitation-contraction coupling (ECC). Upon an action potential, Ca 2+ microdomains, generated in synchrony at the interface between TTs and jSR, underlie the prompt increase in cytosolic Ca 2+ concentration, ultimately responsible for cell contraction during systole. This process requires a considerable amount of energy and the active participation of mitochondria, which encompass ∼30% of the cell volume and represent the major source of ATP in the heart. Importantly, in adult cardiomyocytes, mitochondria are distributed in a highly orderly fashion and strategically juxtaposed with SR. By taking advantage of the vicinity to Ca 2+ releasing sites, they take up Ca 2+ and modulate ATP synthesis according to the specific cardiac workload. Interestingly, with respect to SR, a biased, polarized positioning of mitochondrial Ca 2+ uptake/efflux machineries has been reported, hinting the importance of a strictly regulated mitochondrial Ca 2+ handling for heart activity. This notion, however, has been questioned by the observation that, in some mouse models, the deficiency of specific molecules, modulating mitochondrial Ca 2+ dynamics, triggers non-obvious cardiac phenotypes. This review will briefly summarize the physiological significance of SRmitochondria apposition in cardiomyocytes, as well as the pathological consequences of an altered organelle communication, focusing on Ca 2+ signaling. We will discuss ongoing debates and propose future research directions.

Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

“…Moreover, the exchange of metabolites and/or information between organelles is favoured by their physical proximity, thus making contact areas, i.e., MAM domains in the case of ERmitochondria contacts, the ideal hubs whereby key cellular tasks take place. Therefore, it is not surprising that alterations of organelle contacts and/or functionality have been associated with different pathological conditions, such as diabetes, cancer and neurodegeneration [27,40,[42][43][44][45]. In particular, increasing evidence suggests that disturbances in ER-mitochondria connectivity are early events in neurodegenerative disorders such as Parkinson's disease, amyotrophic lateral sclerosis and AD [46].…”

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

“…The tight connection between the sarco-endoplasmic reticulum (SR/ER) and the mitochondria, also called mitochondria-associated ER membrane (MAM), is essential for the maintenance of energy metabolism, Ca 2+ homeostasis, and cell fate (Rossini and Filadi, 2020 ). The tethering is maintained by mitofusin-2 (MFN2) as well as by a macromolecular complex comprising the SR/ER Ca 2+ channel IP3 receptor 1 (IP3R1) and the porine of the outer membrane of the mitochondria (OMM), VDAC1 (voltage-dependent anion channel 1).…”

Ageing Causes Ultrastructural Modification to Calcium Release Units and Mitochondria in Cardiomyocytes

“…The function of mitochondria and CRUs, besides being important for providing independently ATP and Ca 2+ , is also controlled by their cross-communication: indeed, the importance of a close structural association between intracellular Ca 2+ stores (ER and SR) and mitochondria has been described and discussed extensively in the last couple of decades in both non-excitable and excitable cells [11][12][13][14][15][16][17]. The SR-mitochondria cross-talk in striated tissues has been proposed to be bidirectional [18]: Ca 2+ released by the CRUs enters mitochondria via the mitochondrial Ca 2+ uniporter (MCU) to stimulate the respiratory chain, while the reactive oxygen species (ROS) produced by mitochondria can regulate SR Ca 2+ release [18].…”