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The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Mitochondria and the endoplasmic reticulum (ER) are vital organelles that influence various cellular physiological and pathological processes. Recent evidence shows that about 5%–20% of the mitochondrial outer membrane is capable of forming a highly dynamic physical connection with the ER, maintained at a distance of 10–30 nm. These interconnections, known as MAMs, represent a relatively conserved structure in eukaryotic cells, acting as a critical platform for material exchange between mitochondria and the ER to maintain various aspects of cellular homeostasis. Particularly, ER-mediated Ca2+ release and recycling are intricately associated with the structure and functionality of MAMs. Thus, MAMs are integral in intracellular Ca2+ transport and the maintenance of Ca2+ homeostasis, playing an essential role in various cellular activities including metabolic regulation, signal transduction, autophagy, and apoptosis. The disruption of MAMs observed in certain pathologies such as cardiovascular and neurodegenerative diseases as well as cancers leads to a disturbance in Ca2+ homeostasis. This imbalance potentially aggravates pathological alterations and disease progression. Consequently, a thorough understanding of the link between MAM-mediated Ca2+ transport and these diseases could unveil new perspectives and therapeutic strategies. This review focuses on the changes in MAMs function during disease progression and their implications in relation to MAM-associated Ca2+ transport.

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Fig. 1: Proteins involved in Ca2+ transport of within MAMs.
Fig. 2: Structure of the mitochondrial calcium uniporter (MCU) in MAMs.
Fig. 3: Effect of MAM-related Ca2+ transport on cellular function.
Fig. 4: The relationship between MAM-related calcium transport and cardiovascular diseases is intricate.
Fig. 5: MAMs are implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
Fig. 6: The oncogenes and tumor suppressors involved in inter-organelle Ca2+ transport between ER and mitochondria.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82173811, 81973315), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003), the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD) and Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases.

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    Wen-bin Zhao & Rui Sheng

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Zhao, Wb., Sheng, R. The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01359-9

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