Abstract
The notion of mitochondria being involved in the decoding and shaping of intracellular Ca2+ signals has been circulating since the end of the 19th century. Despite that, the molecular identity of the channel that mediates Ca2+ ion transport into mitochondria remained elusive for several years. Only in the last decade, the genes and pathways responsible for the mitochondrial uptake of Ca2+ began to be cloned and characterized. The gene coding for the pore-forming unit of the mitochondrial channel was discovered exactly 10 years ago, and its product was called mitochondrial Ca2+ uniporter or MCU. Before that, only one of its regulators, the mitochondria Ca2+ uptake regulator 1, MICU1, has been described in 2010. However, in the following years, the scientific interest in mitochondrial Ca2+ signaling regulation and physiological role has increased. This shortly led to the identification of many of its components, to the description of their 3D structure, and the characterization of the uniporter contribution to tissue physiology and pathology. In this review, we will summarize the most relevant achievements in the history of mitochondrial Ca2+ studies, presenting a chronological overview of the most relevant and landmarking discoveries. Finally, we will explore the impact of mitochondrial Ca2+ signaling in the context of muscle physiology, highlighting the recent advances in understanding the role of the MCU complex in the control of muscle trophism and metabolism.
Highlights
Every cell type, in every tissue and at any evolutionary level, can communicate with the surrounding environment and with neighboring cells
We aim to summarize some of the milestone achievements in the history of mitochondrial Ca2+ research with a particular focus on the recent findings of the mitochondrial Ca2+ uniporter and its role in organ physiology
We provided a historical overview of the achievements in the study of mitochondrial Ca2+ signaling
Summary
In every tissue and at any evolutionary level, can communicate with the surrounding environment and with neighboring cells. The increase of the mitochondrial matrix Ca2+ level stimulates both Ca2+ -sensitive dehydrogenases [7,8,9] and respiratory chain complexes [10,11] resident in the organelles, fueling the TCA cycle activity as well as aerobic respiration and boosting the overall oxidative metabolism This makes mitochondria the central hubs for the rapid and effective adaptation of cell metabolism to the changes in energy requirements that are typically decoded as variations of intracellular. Given the extreme relevance of mitochondria Ca2+ signaling for cell physiology, the unveiling of the molecular factors mediating mitochondrial Ca2+ entry and the mechanism(s) of their regulation has been one of the scientific challenges of recent years. Schematic cartoons show the different components of the MCU complex according to the date of their discovery along the timeline
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