Molecular nature and physiological role of the mitochondrial calcium uniporter channel

Calcium (Ca ) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca concentration ([Ca ] ). Mitochondrial Ca uptake is an important determinant of cell fate and governs respiration, mitophagy/autophagy, and the mitochondrial path...

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Published in:American Journal of Physiology: Cell Physiology Vol. 320; no. 4; p. C465
Main Authors: Alevriadou, B Rita, Patel, Akshar, Noble, Megan, Ghosh, Sagnika, Gohil, Vishal M, Stathopulos, Peter B, Madesh, Muniswamy
Format: Journal Article
Language:English
Published: United States 01.04.2021
Subjects:
Animals
Apoptosis
Calcium Channels - chemistry
Calcium Channels - drug effects
Calcium Channels - genetics
Calcium Channels - metabolism
Calcium Signaling - drug effects
Cardiovascular Diseases - drug therapy
Cardiovascular Diseases - genetics
Cardiovascular Diseases - metabolism
Cardiovascular Diseases - pathology
Energy Metabolism - drug effects
Gene Expression Regulation
Humans
Membrane Potential, Mitochondrial
Mitochondria - drug effects
Mitochondria - genetics
Mitochondria - metabolism
Mitochondria - pathology
Mitochondrial Diseases - drug therapy
Mitochondrial Diseases - genetics
Mitochondrial Diseases - metabolism
Mitochondrial Diseases - pathology
Molecular Targeted Therapy
Muscular Diseases - drug therapy
Muscular Diseases - genetics
Muscular Diseases - metabolism
Muscular Diseases - pathology
Neurodegenerative Diseases - drug therapy
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - metabolism
Neurodegenerative Diseases - pathology
Protein Conformation
Reactive Oxygen Species - metabolism
Structure-Activity Relationship
mitochondrial energetics
calcium signaling
reactive oxygen species
mitochondrial calcium uptake
ISSN:1522-1563, 1522-1563
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Summary:Calcium (Ca ) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca concentration ([Ca ] ). Mitochondrial Ca uptake is an important determinant of cell fate and governs respiration, mitophagy/autophagy, and the mitochondrial pathway of apoptosis. Mitochondrial Ca uptake occurs via the mitochondrial Ca uniporter (MCU) complex. This review summarizes the present knowledge on the function of MCU complex, regulation of MCU channel, and the role of MCU in Ca homeostasis and human disease pathogenesis. The channel core consists of four MCU subunits and essential MCU regulators (EMRE). Regulatory proteins that interact with them include mitochondrial Ca uptake 1/2 (MICU1/2), MCU dominant-negative β-subunit (MCUb), MCU regulator 1 (MCUR1), and solute carrier 25A23 (SLC25A23). In addition to these proteins, cardiolipin, a mitochondrial membrane-specific phospholipid, has been shown to interact with the channel core. The dynamic interplay between the core and regulatory proteins modulates MCU channel activity after sensing local changes in [Ca ] , reactive oxygen species, and other environmental factors. Here, we highlight the structural details of the human MCU heteromeric assemblies and their known roles in regulating mitochondrial Ca homeostasis. MCU dysfunction has been shown to alter mitochondrial Ca dynamics, in turn eliciting cell apoptosis. Changes in mitochondrial Ca uptake have been implicated in pathological conditions affecting multiple organs, including the heart, skeletal muscle, and brain. However, our structural and functional knowledge of this vital protein complex remains incomplete, and understanding the precise role for MCU-mediated mitochondrial Ca signaling in disease requires further research efforts.
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ISSN:1522-1563
1522-1563
DOI:10.1152/ajpcell.00502.2020