Mitochondrial calcium (Ca2+) regulation is critically implicated in the regulation of bioenergetics and cell fate. Ca2+, a universal signaling ion, passively diffuses into the mitochondrial ...intermembrane space (IMS) through voltage‐dependent anion channels (VDAC), where uptake into the matrix is tightly regulated across the inner mitochondrial membrane (IMM) by the mitochondrial Ca2+ uniporter complex (mtCU). In recent years, immense progress has been made in identifying and characterizing distinct structural and physiological mechanisms of mtCU component function. One of the main regulatory components of the Ca2+ selective mtCU channel is the mitochondrial Ca2+ uniporter dominant‐negative beta subunit (MCUb). The structural mechanisms underlying the inhibitory effect(s) exerted by MCUb are poorly understood, despite high homology to the main mitochondrial Ca2+ uniporter (MCU) channel‐forming subunits. In this review, we provide an overview of the structural differences between MCUb and MCU, believed to contribute to the inhibition of mitochondrial Ca2+ uptake. We highlight the possible structural rationale for the absent interaction between MCUb and the mitochondrial Ca2+ uptake 1 (MICU1) gatekeeping subunit and a potential widening of the pore upon integration of MCUb into the channel. We discuss physiological and pathophysiological information known about MCUb, underscoring implications in cardiac function and arrhythmia as a basis for future therapeutic discovery. Finally, we discuss potential post‐translational modifications on MCUb as another layer of important regulation.
The mitochondrial calcium uniporter (MCU) is responsible for mitochondrial calcium uptake and homeostasis. It is also a target for the regulation of cellular anti‐/pro‐apoptosis and necrosis by ...several oncogenes and tumour suppressors. Herein, we report the crystal structure of the MCU N‐terminal domain (NTD) at a resolution of 1.50 Å in a novel fold and the S92A MCU mutant at 2.75 Å resolution; the residue S92 is a predicted CaMKII phosphorylation site. The assembly of the mitochondrial calcium uniporter complex (uniplex) and the interaction with the MCU regulators such as the mitochondrial calcium uptake‐1 and mitochondrial calcium uptake‐2 proteins (MICU1 and MICU2) are not affected by the deletion of MCU NTD. However, the expression of the S92A mutant or a NTD deletion mutant failed to restore mitochondrial Ca2+ uptake in a stable MCU knockdown HeLa cell line and exerted dominant‐negative effects in the wild‐type MCU‐expressing cell line. These results suggest that the NTD of MCU is essential for the modulation of MCU function, although it does not affect the uniplex formation.
Synopsis
This study reports the crystal structures of the N‐terminal domain (NTD) of wild‐type and a S92A mutant form of MCU. Functional analyses suggest that the N‐terminal domain of MCU is essential for the modulation of MCU activity.
Crystal structures of the NTD of WT and a S92A mutant form of MCU were determined.
The structure of MCU NTD contains a novel fold important for post‐translational modifications.
Functional analysis suggests that MCU NTD is essential for the modulation of MCU activity.
This study reports the crystal structures of the N‐terminal domain (NTD) of wild‐type and a S92A mutant form of MCU. Functional analyses suggest that the N‐terminal domain of MCU is essential for the modulation of MCU activity.
Ca2+ Fluxes and Cancer Marchi, Saverio; Giorgi, Carlotta; Galluzzi, Lorenzo ...
Molecular cell,
06/2020, Volume:
78, Issue:
6
Journal Article
Peer reviewed
Open access
Ca2+ ions are key second messengers in both excitable and non-excitable cells. Owing to the rather pleiotropic nature of Ca2+ transporters and other Ca2+-binding proteins, however, Ca2+ signaling has ...attracted limited attention as a potential target of anticancer therapy. Here, we discuss cancer-associated alterations of Ca2+ fluxes at specific organelles as we identify novel candidates for the development of drugs that selectively target Ca2+ signaling in malignant cells.
Marchi et al. discuss cancer-associated alterations of Ca2+ fluxes at specific organelles as they identify novel candidates for the development of drugs that selectively target Ca2+ signaling in malignant cells.
The agricultural sector is facing significant challenges in meeting the increasing demands for food production while ensuring sustainability and resource efficiency. To address these challenges, the ...integration of Internet of Things (IoT) technology into farming practices has gained attention as a promising solution. This research focuses on the development and implementation of an IoT-enabled smart farming system aimed at enhancing crop growth efficiency. The proposed system leverages IoT sensors and devices to monitor and collect real-time data on various parameters such as environmental conditions, soil moisture levels, and crop health. The collected data is then analyzed using advanced analytics techniques to gain valuable insights and make informed decisions regarding irrigation, fertilization, and pest control. By utilizing IoT technology, farmers can optimize their resource utilization, reduce waste, and maximize crop productivity. This research aims to investigate the potential benefits and challenges associated with implementing the IoT-enabled smart farming system. In this paper, a cutting-edge Internet of Things (IoT) technology is explored for monitoring weather and soil conditions for efficient crop development. The system was built to monitor temperature, humidity, and soil moisture using Node MCU and several linked sensors. Additionally, a Wi-Fi connection is used to send a notification through SMS to the farmer's phone about the field's environmental state. The results will help in developing strategies and guidelines for the widespread adoption of IoT-enabled smart farming practices, ultimately leading to sustainable and efficient crop production to meet the demands of a growing population.
The MCU complex in cell death Penna, Elisa; Espino, Javier; De Stefani, Diego ...
Cell calcium (Edinburgh),
January 2018, 2018-01-00, 20180101, Volume:
69
Journal Article
Peer reviewed
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During the 60s, the notion that positively charged Ca2+ ions are rapidly accumulated in energized mitochondria has been first established. In the following decades, mitochondrial Ca2+ ...homeostasis was shown to control cell metabolism, cell survival and other cell-specific functions through different mechanism. However, the molecular identity of the molecules controlling this process remained a mystery until just few years ago, when both mitochondrial Ca2+ uptake and release systems were genetically dissected. This finally opened the possibility to develop genetic model to directly test the contribution of mitochondrial Ca2+ homeostasis to cellular functions. Although the picture is still far from being clear, we here summarize and critically evaluate the current knowledge on how mitochondrial Ca2+ handling controls cell death.
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•MCU-C3N4 was fabricated by supramolecular strategy.•MCU-C3N4/PVDF membranes were assembled by vacuum filtration with crosslinkers.•MCU-C3N4/PVDF membranes had excellent ...photocatalytic degradation of RhB and TC.•MCU-C3N4/PVDF membranes exhibited well self-cleaning properties.
Recently, the application of membranes faces a big challenge due to membrane fouling, to alleviate this situation, the hybridization of photocatalysis and membrane filtration has aroused significant attention. In this study, we firstly introduced melamine, cyanuric acid and urea in dimethyl sulfoxide (DMSO) as precursors to fabricated the MCU(DMSO)-C3N4 material with excellent photocatalytic performance, and immobilized it on PVDF membranes by vacuum filtration, subsequently adding polyethylene glycol and glutaraldehyde as crosslinkers from MCU-C3N4/PVDF membrane. The results demonstrate that with the MCU-C3N4 ratio increasing, the membrane flux was gradually decreased. Besides, the photocatalytic efficiencies of MCU-C3N4/PVDF for rhodamine B (RhB) and tetracycline hydrochloride (TC) degradation are 84.24% and 71.26% respectively, which are about 8 times higher than that of the original membrane. To evaluate antifouling performance of photocatalytic membranes, we conducted a four-stage filtration system, and the flux recovery ratio (FRR) of MCU-C3N4/PVDF membranes reached over 80% (optimum 91%) under visible light irradiating (λ > 420 nm) for 30 min. Meanwhile, under visible light irradiation reversible fouling (Rr) gradually became the dominant fouling factor instead of the irreversible fouling (Rir), indicating the excellent antifouling performance of MCU-C3N4/PVDF membranes. This novel method to modify membranes with MCU-C3N4 gives insight to photocatalytic and self-cleaning properties of photocatalytic composite membranes, providing theoretical basis for their broad application.
Ca2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated ...in mitochondria. Whether and how these coactive elements interact with MCU have not been established. As an approach toward understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 (Cys-97) to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural, and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher Ca2+m uptake rate, elevated mROS, and enhanced Ca2+m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity.
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•Mitochondrial Ca2+ uniporter complex core component senses mitochondrial ROS•MCU Cys-97 undergoes S-glutathionylation and exhibits as a higher-order oligomer•Interaction between MCU and its regulatory components is unaltered by MCU oxidation•Inflammatory/hypoxia signals promote MCU oxidation and sensitize cells to death
Dong et al. show that conserved MCU Cys-97 senses mitochondrial luminal ROS, and MCU oxidation promotes MCU higher-order oligomer formation and exhibits persistent activation of the MCU channel, elevated mitochondrial ROS, and enhanced Ca2+m overload-induced cell death. These findings reveal a distinct functional role for Cys-97 in mROS sensing and regulation of MCU activity.
Recently, the application of membranes faces a big challenge due to membrane fouling, to alleviate this situation, the hybridization of photocatalysis and membrane filtration has aroused significant ...attention. In this study, we firstly introduced melamine, cyanuric acid and urea in dimethyl sulfoxide (DMSO) as precursors to fabricated the MCU(DMSO)-C
N
material with excellent photocatalytic performance, and immobilized it on PVDF membranes by vacuum filtration, subsequently adding polyethylene glycol and glutaraldehyde as crosslinkers from MCU-C
N
/PVDF membrane. The results demonstrate that with the MCU-C
N
ratio increasing, the membrane flux was gradually decreased. Besides, the photocatalytic efficiencies of MCU-C
N
/PVDF for rhodamine B (RhB) and tetracycline hydrochloride (TC) degradation are 84.24% and 71.26% respectively, which are about 8 times higher than that of the original membrane. To evaluate antifouling performance of photocatalytic membranes, we conducted a four-stage filtration system, and the flux recovery ratio (FRR) of MCU-C
N
/PVDF membranes reached over 80% (optimum 91%) under visible light irradiating (λ > 420 nm) for 30 min. Meanwhile, under visible light irradiation reversible fouling (Rr) gradually became the dominant fouling factor instead of the irreversible fouling (Rir), indicating the excellent antifouling performance of MCU-C
N
/PVDF membranes. This novel method to modify membranes with MCU-C
N
gives insight to photocatalytic and self-cleaning properties of photocatalytic composite membranes, providing theoretical basis for their broad application.
•Mrs2 is an integral membrane protein.•Mrs2 localizes to the inner mitochondrial membrane with its N and C-termini in the matrix.•Mrs2 is crucial in regulating mitochondrial Mg2+ uptake and cytosolic ...Mg2+ dynamics.•The loss of mitochondrial Mg2+ uptake leads to the activation of MCU-mediated mitochondrial Ca2+ uptake.•The loss of Mrs2 activates MCU in the low-iCa2+ regime.•Fine-tuning of MCU activity and Ca2+-mediated mPTP opening is accomplished by Mrs2-mediated mMg2+ uptake.
Mitochondrial Ca2+ uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here, we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed that decreased matrix Mg2+ is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg2+ in regulating MCU activity.
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