Abstract
In the last few decades, a large body of experimental evidence has highlighted the complex role for mitochondria in eukaryotic cells: they are not only the site of aerobic metabolism (thus providing most of the ATP supply for endergonic processes) but also a crucial checkpoint of cell death processes (both necrosis and apoptosis) and autophagy. For this purpose, mitochondria must receive and decode the wide variety of physiological and pathological stimuli impacting on the cell. The “old” notion that mitochondria possess a sophisticated machinery for accumulating and releasing Ca 2+, the most common and versatile second messenger of eukaryotic cells, is thus no surprise. What may be surprising is that the identification of the molecules involved in mitochondrial Ca 2+ transport occurred only in the last decade for both the influx (the mitochondrial Ca 2+ uniporter, MCU) and the efflux (the sodium calcium exchanger, NCX) pathways. In this review, we will focus on the description of the amazing molecular complexity of the MCU complex, highlighting the numerous functional implications of the tissue-specific expression of the variants of the channel pore components (MCU/MCUb) and of the associated proteins (MICU 1, 2, and 3, EMRE, and MCUR1).
Highlights
Ca2+ is universally recognised as one of the most pleiotropic second messengers in cell biology
Ca2+ ions are responsible for decoding a variety of extracellular and intracellular stimuli, which, in animals, range from endocrine secretion to gene expression, muscle contraction, and synaptic transmission[1,2,3,4,5]
Cardiac-specific tamoxifen-inducible mitochondrial Ca2+ uniporter (MCU) deletion in adult mice, differently from the germline genetic ablation of MCU, which did not protect from ischemic-reperfusion injury[34], clearly protects from ischemia-reperfusion heart damage, abrogates the contractile responsiveness to β-adrenergic stimulation responsible for the so-called “fight-or-flight” response, and reduces heart bioenergetics reserve capacity, even though it does not induce phenotypic abnormalities either in basal conditions or after cardiac overload and does not alter cardiomyocytes’ resting [Ca2+] . 36–39 These results suggest that MCU may be dispensable mt for cardiac homeostasis in basal conditions, while it appears to play a major role in cardiac metabolic flexibility during acute stress
Summary
Ca2+ is universally recognised as one of the most pleiotropic second messengers in cell biology. Mitoxantrone has been utilised already in clinical practice for its antineoplastic action against non-Hodgkin’s lymphomas and acute myeloid leukaemia[86]; the anti-tumour properties of this drug appear to rely on a different molecular moiety with respect to its anti-MCU activity, opening up the possibility for the chemical engineering of new lead compounds to target MCU function This is of outmost relevance for the design of novel potential therapeutic approaches to pathologies in which mitochondrial Ca2+ signalling dysfunction is involved[17,87,88], including those characterised by primary MCU dysfunction due to mutations in its components[50,52,53]. Despite many of the molecular mechanisms refining MCU activity in the cell having been described, of which the most relevant are presented in this review, a number of other possibilities for the modulation of uniporter function may exist (at transcriptional and post-transcriptional levels), and additional efforts are needed from the scientific community to fully unravel the complexity of mitochondrial Ca2+ uptake regulation
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