• The MCU is one of the primary sources of mitochondria uptake of calcium, and flow is dependent on membrane potential of the inner mitochondrial membrane and the concentration of calcium in the cytosol relative to the concentration in the mitochondria. (wikipedia.org)
  • The mitochondrial calcium uptake 1 (MICU1) is a single pass membrane protein, it contains 2 binding domains. (wikipedia.org)
  • Mitochondrial calcium uptake 2 (MICU2) is another intermitochondrial membrane protein. (wikipedia.org)
  • We here show that expression of the mitochondrial calcium uniporter (MCU), the selective channel responsible for mitochondrial Ca(2+) uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca(2+) uptake might be instrumental for tumor growth and metastatic formation. (nih.gov)
  • Our results indicate that MCU plays a central role in TNBC growth and metastasis formation and suggest that mitochondrial Ca(2+) uptake is a potential novel therapeutic target for clinical intervention. (nih.gov)
  • Global knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) abrogates rapid mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening, but does not protect from ischemic injury. (nih.gov)
  • Mitochondrial Ca 2+ uptake was found to be mediated by the mitochondrial Ca 2+ uniporter (MCU). (alomone.com)
  • MCUB fine-tunes calcium uptake by mitochondria in injured heart tissue, in an attempt to limit calcium overload, which is a major contributor to cell death, particularly following a heart attack," explained John W. Elrod, PhD, Associate Professor in the Center for Translational Medicine at the Temple University Lewis Katz School of Medicine and senior investigator on the new study. (sciencedaily.com)
  • Just like an emergency responder, MCUB moves in and tries to reduce cell death and aid cell survival -- however, the reduction in mitochondrial calcium uptake is also maladaptive and limits the cell's ability to increase energy during stress. (sciencedaily.com)
  • We think that modulating MCUB may allow us to tune down mitochondrial calcium uptake without completely inhibiting all energetic function. (sciencedaily.com)
  • The mitochondrial calcium uniporter (MCU) mediates mitochondrial calcium uptake, a process of utmost physiological importance, especially in tissues with high energy demands such as skeletal muscle. (tum.de)
  • Upregulation of MCUb limits mitochondrial matrix Ca 2+ uptake and impairs mitochondrial energy production via glucose oxidation by depressing pyruvate dehydrogenase complex activity. (diabetesjournals.org)
  • Crosstalk between Mitochondrial Ca2+ Uptake and Autophagy in Skeletal Muscle. (unipd.it)
  • No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele. (ncl.ac.uk)
  • The mitochondrial calcium uniporter (MCU) is a transmembrane protein that allows the passage of calcium ions from a cell's cytosol into mitochondria. (wikipedia.org)
  • The MCU has a very low affinity for calcium, so the cytosolic calcium concentration needs to be approximately 5-10 uM for significant transport of calcium into the mitochondria. (wikipedia.org)
  • Mitochondria are closely associated with the endoplasmic reticulum (ER), at contact sites, which contains stores of cellular calcium ions for calcium signaling. (wikipedia.org)
  • The presence of 1,4,5-triphosphate (IP3) triggers the release of calcium from these intracellular stores, which creates microdomains of high calcium concentration between the ER and the mitochondria, creating the conditions for the MCU to take up calcium. (wikipedia.org)
  • However, along with limiting the entry of calcium into the mitochondrial matrix, it functions alongside MCU to keep the accumulated calcium inside the matrix of the mitochondria, and promotes ion specificity by preventing aberrant loading of transition metals into the mitochondria. (wikipedia.org)
  • As part of this process, researchers show for the first time that one of these specialized emergency responder proteins, known as MCUB, temporarily decreases harmful levels of calcium transport into mitochondria, the energy-generating batteries of cells. (sciencedaily.com)
  • Calcium homeostasis is vital to a number of day-to-day cellular activities and is regulated primarily by mitochondria. (sciencedaily.com)
  • For calcium to enter mitochondria, it passes through a channel known as the mitochondrial calcium uniporter (MCU), which resides in the inner mitochondrial membrane where it stimulates the production of ATP, the energy currency of the cell. (sciencedaily.com)
  • The amount of calcium that mitochondria take up is regulated by various components of this channel. (sciencedaily.com)
  • In particular, their mitochondria - visualized here by presence of the mitochondrial calcium uniporter protein in yellow - are larger and more abundant in certain regions of the cell. (neurosciencenews.com)
  • Findings have implicated mitochondria in a wide variety of cellular processes and molecular interactions, such as calcium buffering, lipid flux, and intracellular signaling. (biomedcentral.com)
  • The difficulty in understanding and treating human pathologies caused by mitochondrial dysfunction arises from the complex relationships between mitochondria and other cellular processes, as well as the genetic background of such diseases. (biomedcentral.com)
  • In this study, we introduced a light-driven proton transporter, Delta-rhodopsin (dR), to Drosophila mitochondria, where the mitochondrial proton-motive force (Δp) and mitochondrial membrane potential are maintained in a light-dependent manner. (nature.com)
  • Light-dependent activation of mitochondrion-targeted dR (mito-dR) but not a mito-dR inactive mutant successfully transformed mitochondria from an OXPHOS-dependent powerhouse to a photoenergetic powerhouse, which accordingly reinforced the mitochondrial functions of the nerve terminals in terms of ATP production and Ca 2+ -buffering activity, suppressing ROS generation 10 , 11 . (nature.com)
  • It can enter mitochondria via the calcium uniporter and inhibit mitochondrial oxidative phosphorylation. (selfdecode.com)
  • Plant uncoupling mitochondrial protein activity in mitochondria isolated from tomatoes at different stages of ripening. (shengsci.com)
  • The proteins MCU and EMRE form the minimal functional unit of the mitochondrial calcium uniporter complex in metazoans, a highly selective and tightly controlled Ca 2+ channel of the inner mitochondrial membrane that regulates cellular metabolism. (biorxiv.org)
  • Subsequently, acyl-carnitines are translocated across the inner mitochondrial membrane by cartinine acyl translocase. (biomedcentral.com)
  • We find that OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies. (biorxiv.org)
  • The mETC is comprised of a series of four large inner mitochondrial membrane (IMM) complexes (CI-CIV) that assemble into supercomplexes of defined stoichiometry ( Letts and Sazanov, 2017 ). (biorxiv.org)
  • CHCHD2 (mutations of which cause an autosomal dominant form of PD) encodes a mitochondrial intermembrane protein 1 . (nature.com)
  • To identify determinants of mETC function, we screened a genome-wide human CRISPRi library under oxidative metabolic conditions with selective inhibition of mitochondrial Complex III and identified OCIA domain-containing protein 1 (OCIAD1) as a Complex III assembly factor. (biorxiv.org)
  • Functional analysis in the patient fibroblasts included oxygen consumption measurements, extracellular acidification studies, Western blotting, and calcium imaging, followed by overexpression of the wild-type protein. (ncl.ac.uk)
  • Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer's disease. (harvard.edu)
  • The Conserved Aspartate Ring of MCU Mediates MICU1 Binding and Regulation in the Mitochondrial Calcium Uniporter Complex. (cuanschutz.edu)
  • The mitochondrial Ca2+ uniporter (MCU) complex mediates acute mitochondrial Ca2+ influx. (jci.org)
  • Zhang H, Zhu Y, Suehiro Y, Mitani S, Xue D. AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations. (ucdenver.edu)
  • Now, we're particularly interested in calcium signalling pathways and how calcium mediates these kind of effects. (hstalks.com)
  • This review attempts to provide a summary of the background knowledge and recent developments in mitochondrial processes relating to mitochondrial-associated metabolic diseases arising from defects or deficiencies in mitochondrial function, as well as insights into current and future avenues for investigation. (biomedcentral.com)
  • The contribution of altered mitochondrial Ca 2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. (diabetesjournals.org)
  • Its activity is regulated by MICU1 and MICU2, which together with the MCU make up the mitochondrial calcium uniporter complex. (wikipedia.org)
  • MICU1 helps to stabilize the entire mitochondrial calcium uniporter complex, it also limits the amount of calcium that enters the cell during low concentrations of calcium. (wikipedia.org)
  • It is also shown that all three, MCU, MICU1, and MICU2 are part of a single complex, the mitochondrial calcium uniporter complex resumes. (wikipedia.org)
  • Proteolytic Control of the Mitochondrial Calcium Uniporter Complex. (cuanschutz.edu)
  • In this study, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. (diabetesjournals.org)
  • One of the underlying mechanisms of long COVID may be mitochondrial dysfunction. (mdpi.com)
  • Drosophila CHCHD2 ( dCHCHD2 ) knockout flies exhibit PD-like phenotypes in an age-dependent manner, which include dysfunction in motor ability, DA neuron loss, increased oxidative stress and mitochondrial cristae degeneration 2 . (nature.com)
  • Dysfunction of the mitochondrial electron transport chain (mETC) is a major cause of human mitochondrial diseases. (biorxiv.org)
  • While MCUB closely resembles the pore forming subunit, MCU, its precise role in calcium regulation is largely unknown, particularly in the context of disease. (sciencedaily.com)
  • Tsai MF , Phillips CB, Ranaghan M, Tsai CW, Williams C, & Miller C. Dual Functions of a Small Regulatory Subunit in the Mitochondrial Calcium Uniporter. (cuanschutz.edu)
  • abstract = "The effects of global mitochondrial calcium (Ca2+) uniporter (MCU) deficiency on hypoxic-ischemic (HI) brain injury, neuronal Ca2+ handling, bioenergetics and hypoxic preconditioning (HPC) were examined. (nyu.edu)
  • Mn(II) has been shown to inhibit mitochondrial aconitase activity to a significant level, altering amino acid metabolism and cellular iron homeostasis. (selfdecode.com)
  • Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance. (unipd.it)
  • This was achieved by expressing an enzyme that prevented Ca 2+ release from inositol 1,4,5-trisphosphate receptors, inhibition of mitochondrial respiration, and knockdown of the mitochondrial Ca 2+ uniporter. (open.ac.uk)
  • The mitochondrial calcium uniporter is a highly selective ion channel. (yale.edu)
  • This idea is supported by the discovery that many genetic mutations associated with PD appear to be associated in some way with mitochondrial dynamics or oxidative stress (e.g. (frontiersin.org)
  • In the present work, a novel function of MCU as a mitochondrial redox modulator with downstream effects on energy metabolism and muscle performance was discovered. (tum.de)
  • Szabo G, Hoek JB, Darley-Usmar V, Hajnoczky G, Knudsen T, Mochly-Rosen D, Zakhari S. RSA 2004: combined basic research satellite symposium - session three: alcohol and mitochondrial metabolism: at the crossroads of life and death. (jefferson.edu)
  • MICU1 was used as a bait to figure out what the core of the mitochondrial calcium uniporter was. (wikipedia.org)
  • MICU2 works with MICU1 and MCU to reduce the amount of calcium coming into the matrix. (wikipedia.org)
  • however, whenever MICU1 is sequestered and MICU2 is activated, normal calcium flow. (wikipedia.org)
  • MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle. (ncl.ac.uk)
  • The fluctuating clinical course is likely mediated through the mitochondrial calcium uniporter, which is regulated by MICU1. (ncl.ac.uk)
  • The proton flow responsible for decreased pH values inside mitochondrial cristae and membrane invaginations of cyanobacteria has been c. (shengsci.com)
  • It is hoped that follow-up studies defining the exact sites of molecular interaction will provide additional insight into how to target mitochondrial calcium overload in heart disease. (sciencedaily.com)
  • OXPHOS depends on the mitochondrial electron transport chain (mETC), which transfers electrons from NADH and succinate to molecular oxygen. (biorxiv.org)
  • But here we uncovered mitochondrial heterogeneity within a single brain cell," said Farris, who also has an appointment in the Virginia-Maryland College of Veterinary Medicine. (neurosciencenews.com)
  • As electrons are shuttled through the complexes I, III and IV by electron carriers, protons (H + ) are moved from the mitochondrial matrix into the intermembrane space. (biomedcentral.com)
  • Fatty acids, which are often found in chains as CoA-esters, are first transported across the outer mitochondrial membrane by palmitoyl transferase I, resulting in translocation to the intermembrane space and transformation into an acyl-carnitine form. (biomedcentral.com)
  • Ruthenium red and Ru360 are typical reagents used to experimentally block the MCU to study its properties and role in mitochondrial signaling. (wikipedia.org)
  • Dr. Elrod's team found that deletion of the MCUB gene in cells results in a change in the proteins that make up the calcium channel and that are essential for controlling whether the channel is on or off. (sciencedaily.com)
  • The loss of the PD-associated mitochondrial gene CHCHD2 resulted in reduced ATP production, enhanced mitochondrial peroxide production and lower Ca 2+ -buffering activity in dopaminergic (DA) terminals in flies. (nature.com)
  • The new research, published online September 19 in the journal Circulation , identifies MCUB as a promising new target for the investigation and treatment of conditions that feature calcium overload and cell death -- conditions that include heart failure, heart attack, stroke, and neurodegeneration. (sciencedaily.com)
  • When genetically expressed prior to inducing a heart attack in mice, MCUB altered the channel to reduce calcium overload in the injured heart, ultimately curtailing tissue injury. (sciencedaily.com)
  • Dr. Elrod's team also found that, while it can improve cell survival after heart injury, increased MCUB activity comes at the expense of mitochondrial energy production. (sciencedaily.com)
  • In MCU-silenced cells, production of mitochondrial reactive oxygen species (mROS) is blunted and expression of the hypoxia-inducible factor-1α (HIF-1α) is reduced, suggesting a signaling role for mROS and HIF-1α, downstream of mitochondrial Ca(2+) Finally, in breast cancer mRNA samples, a positive correlation of MCU expression with HIF-1α signaling route is present. (nih.gov)
  • The researchers will also genetically knock out specific mitochondrial genes to better define how certain mitochondrial properties uniquely impact social memory and behavior in mice. (neurosciencenews.com)
  • And one particular focus in the lab is on an important source of calcium influx, the NMDA subtype of ionotrophic glutamate receptors. (hstalks.com)
  • So a typical glutamatergic synapse, such as the one shown in the cartoon here, the NMDA receptor is a very important source of activity-dependent calcium influx. (hstalks.com)
  • So it wasn't until the mid-1980s that the major cause of glutamate excitotoxity was pinned down by Choi, Meldrum, and others as being due to calcium influx into the neurons. (hstalks.com)
  • And that this calcium influx was mediated by the NMDA receptor, the NMDA subtype of ionotrophic glutamate receptors. (hstalks.com)
  • This study suggests the enhancement of Δp by mito-dR as a therapeutic mechanism that ameliorates neurodegeneration by protecting mitochondrial functions. (nature.com)
  • Elevation of cytosolic Ca 2+ with glutamate or ionomycin decreased PDH phosphorylation in MCU null neurons suggesting the use of alternative mitochondrial Ca 2+ transport. (nyu.edu)
  • She hypothesizes that these unusual mitochondrial characteristics may be influencing this brain region's plasticity - or ability to rapidly modify synapses, neurochemical portals that mediate communication between neurons. (neurosciencenews.com)
  • Tsai MF , Jiang D, Zhao L, Clapham D, & Miller C. Functional Reconstitution of the Mitochondrial H+/Ca2+ Exchanger Letm1. (cuanschutz.edu)
  • Mitochondrial Calcium Uniporter Affects Neutrophil Bactericidal Activity during Staphylococcus aureus Infection. (jefferson.edu)
  • And it's this calcium that is a major mediator of the neuroprotective, as well as the toxic effects of NMDA receptor activity. (hstalks.com)
  • The Barth Syndrome (BTHS) is caused by the loss of the mitochondrial acyltransferase tafazzin, which is involved in the remodeling process of the hallmark mitochondrial glycerophospholipid cardiolipin. (uni-goettingen.de)
  • It may also inhibit the efflux of Ca(II), which can result in a loss of mitochondrial membrane integrity. (selfdecode.com)
  • Improved mitochondrial functions are expected to be a promising therapeutic strategy for PD. (nature.com)