Document Type

Article

Publication Date

8-1-2025

Comments

This article is the author’s final published version in American Journal of Physiology - Cell Physiology, Volume 329, Issue 2, 2025, Pages C599-C610.

The published version is available at https://doi.org/10.1152/ajpcell.00435.2025. Copyright © 2025 The Authors.

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, Ca 2 þ , 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 cardiomy- ocytes (CMs) in vivo revealed the importance of the microdomains between mitochondria and sarcoplasmic reticulum (SR), a dif- ferentiated form of ER in muscle cells, for maintaining normal mitochondrial Ca 2 þ (mtCa 2 þ ) 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 Ca 2 þ 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 develop- ment and progression of cardiac pathology.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

40643460

Language

English

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