Sarcoplasmic reticulum-mitochondria microdomains: hugging and kissing in the heart

Abstract

Endoplasmic reticulum (ER)-mitochondrial (ER-Mito) interface, termed mitochondrial-ER contacts (MERCs), plays significant roles in the maintenance of bioenergetics and basal cell functions via the exchange of lipids, Ca²⁺, and reactive oxygen species (ROS) in various cell types/tissues. Genetic deletion of mitofusin 2 (Mfn2), one of the key components of ER-Mito tethering, in cardiomyocytes (CMs) in vivo revealed the importance of the microdomains between mitochondria and sarcoplasmic reticulum (SR), a differentiated form of ER in muscle cells, for maintaining normal mitochondrial Ca²⁺ (mtCa²⁺) handling and bioenergetics in the adult heart. However, key questions remain to be answered: 1) What tethering proteins sustain SR-Mito contact site structure in SR-Mito contact sites in the adult ventricular CMs (AVCMs), the predominant cell type in the adult heart? 2) Which MERC proteins operate in AVCMs to mediate specific microdomain functions under physiological conditions? and 3) How are the MERC protein expression profile and function altered in cardiac pathophysiology? In this review, we summarize current knowledge regarding the structure, function, and regulation of SR-Mito microdomains in the heart, with particular focus on AVCMs, which display unique membrane organization and Ca²⁺ handling compared with other cell types. We further explore molecular mechanisms underpinning microdomain dysfunction in cardiac diseases and highlight the emerging roles of MERC proteins in the development and progression of cardiac pathology.

Keywords: IP3 receptor; calcium; cardiac myocyte; mitochondria-associated membrane; ryanodine receptor.

Fig. 1.. Structural difference in Ca²⁺ transport system at MERCs in adult ventricular cardiomyocytes (AVCMs) and non-AVCMs.

A. Schematic diagrams of MERC Ca²⁺ transport system in non-CM (top) and AVCMs (bottom). Major Ca²⁺ releasing units of ER (i.e., IP₃Rs) face towards mitochondria, whereas major Ca²⁺ releasing unit of SR (i.e., RyR2) face towards T-Tubules. The Ca²⁺ concentration after the ER/SR Ca²⁺ release was shown as heat maps. Distributions of MCU and NCLX within the mitochondria in AVCMs are simplified, and the SR-Ca²⁺ uptake system is abbreviated (see details in Section 3.1). B. Summary of the key differences in the structural MERC Ca²⁺ transport system in AVCMs and non-CMs.

Fig. 2.. Structural alterations of SR-Mito microdomains in the adult ventricular cardiomyocytes and their potential impact on the cardiac functions under pathophysiological conditions

A. Physiological mtCa²⁺ loading via SR-Mito microdomains and mtCUC is required for the "fight-or-flight" response that enables the heart to match its workload with ATP production. B. The mtCa²⁺ overload via cytosolic Ca²⁺ elevation and narrowed SR-Mito contact sites under I/R promotes mitochondrial depolarization, ROS generation, mPTP opening, and apoptotic signaling activation. C. The mtCa²⁺ reduction due to the wide SR-Mito contact sites in heart failure causes lower ATP production and higher mitochondrial ROS generation.