A Review of the Role of Endo/Sarcoplasmic Reticulum-Mitochondria Ca2+ Transport in Diseases and Skeletal Muscle Function

Abstract

The physical contact site between a mitochondrion and endoplasmic reticulum (ER), named the mitochondria-associated membrane (MAM), has emerged as a fundamental platform for regulating the functions of the two organelles and several cellular processes. This includes Ca²⁺ transport from the ER to mitochondria, mitochondrial dynamics, autophagy, apoptosis signalling, ER stress signalling, redox reaction, and membrane structure maintenance. Consequently, the MAM is suggested to be involved in, and as a possible therapeutic target for, some common diseases and impairment in skeletal muscle function, such as insulin resistance and diabetes, obesity, neurodegenerative diseases, Duchenne muscular dystrophy, age-related muscle atrophy, and exercise-induced muscle damage. In the past decade, evidence suggests that alterations in Ca²⁺ transport from the ER to mitochondria, mediated by the macromolecular complex formed by IP₃R, Grp75, and VDAC1, may be a universal mechanism for how ER-mitochondria cross-talk is involved in different physiological/pathological conditions mentioned above. A better understanding of the ER (or sarcoplasmic reticulum in muscle)-mitochondria Ca²⁺ transport system may provide a new perspective for exploring the mechanism of how the MAM is involved in the pathology of diseases and skeletal muscle dysfunction. This review provides a summary of recent research findings in this area.

Keywords: endo/sarcoplasmic reticulum-mitochondria Ca2+ transport; mitochondria-associated membrane; mitochondrial calcium overload; skeletal muscle function.

Figure 1

The changes in ER/SR-mitochondrial Ca²⁺ transport mediated by IP₃R-Grp75-VDAC1 that are involved in diseases and skeletal muscle dysfunction. Under normal physiological conditions, parts of the mitochondrial membrane are physically connected to the ER/SR. The ER/SR-mitochondria Ca²⁺ transport is mediated by the macromolecular complex IP₃R-Grp75-VDAC1 and supplies Ca²⁺ to mitochondria for ATP production. However, an increase in ER/SR-mitochondria Ca²⁺ transport is involved in diseases such as Alzheimer’s disease, hepatic diabetes, heart ischemia/reperfusion injury, and skeletal muscle impairment. A decrease in the ER/SR-mitochondria Ca²⁺ transport is also a contributing factor for Parkinson’s disease, insulin resistance in the liver, and muscle performance reduction.

Figure 2

SR-mitochondria Ca²⁺ transport in skeletal muscle. The terminals of the SR are located near the T-tubules. Mitochondria are located close to the CRU on both sides of the Z-line within the I-band. (A) At rest, RyR releases no Ca²⁺. (B) Upon membrane depolarization, the conformational change of RyR causes Ca²⁺ release from the SR to cytosol (triggering muscle contraction) and hypothetically transported to mitochondria via the IP₃R-Grp75-VDAC1 pathway (required by ATP production).