Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca2+

Mitochondrial Ca2+ uptake is a vital process that controls distinct cell and organelle functions. Mitochondrial calcium uptake 1 (MICU1) was identified as key regulator of the mitochondrial Ca2+ uniporter (MCU) that together with the essential MCU regulator (EMRE) forms the mitochondrial Ca2+ channel. However, mechanisms by which MICU1 controls MCU/EMRE activity to tune mitochondrial Ca2+ signals remain ambiguous. Here we established a live-cell FRET approach and demonstrate that elevations of cytosolic Ca2+ rearranges MICU1 multimers with an EC50 of 4.4 μM, resulting in activation of mitochondrial Ca2+ uptake. MICU1 rearrangement essentially requires the EF-hand motifs and strictly correlates with the shape of cytosolic Ca2+ rises. We further show that rearrangements of MICU1 multimers were independent of matrix Ca2+ concentration, mitochondrial membrane potential and expression levels of MCU and EMRE. Our experiments provide novel details about how MCU/EMRE is regulated by MICU1 and an original approach to investigate MCU/EMRE activation in intact cells.

• Publication year

  2015

• Venue

  Scientific Reports

• Publication date

  2015-10-22

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/srep15602PMID 26489515PMCID 4615007
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The mitochondrial Ca(2+) uniporter complex.

  2015cited by this paper
• Molecular control of mitochondrial calcium uptake.

  2014cited by this paper
• Molecular mechanism of mitochondrial calcium uptake

  2014cited by this paper
• Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake

  2014cited by this paper
• Regulation of the mitochondrial Ca(2+) uniporter by MICU1 and MICU2.

  2014cited by this paper
• MICU1 and MICU2 Finely Tune the Mitochondrial Ca2+ Uniporter by Exerting Opposite Effects on MCU Activity

  2014cited by this paper
• The uniporter: from newly identified parts to function.

  2014cited by this paper
• MICU1 motifs define mitochondrial calcium uniporter binding and activity.

  2013cited by this paper
• Molecularly Distinct Routes of Mitochondrial Ca2+ Uptake Are Activated Depending on the Activity of the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA)

  2013cited by this paper
• MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter.

  2013cited by this paper
• MICU2, a Paralog of MICU1, Resides within the Mitochondrial Uniporter Complex to Regulate Calcium Handling

  2013cited by this paper
• EMRE Is an Essential Component of the Mitochondrial Calcium Uniporter Complex

  2013cited by this paper
• The mitochondrial calcium uniporter is a multimer that can include a dominant‐negative pore‐forming subunit

  2013cited by this paper
• Spatiotemporal Correlations between Cytosolic and Mitochondrial Ca2+ Signals Using a Novel Red-Shifted Mitochondrial Targeted Cameleon

  2012cited by this paper
• MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival.

  2012cited by this paper
• MCUR1 is an Essential Component of Mitochondrial Ca2+ Uptake that Regulates Cellular Metabolism

  2012cited by this paper
• Leucine Zipper EF Hand-containing Transmembrane Protein 1 (Letm1) and Uncoupling Proteins 2 and 3 (UCP2/3) Contribute to Two Distinct Mitochondrial Ca2+ Uptake Pathways

  2011cited by this paper
• Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter

  2011cited by this paper
• Faculty Opinions recommendation of A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.

  2011cited by this paper
• A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter

  2011cited by this paper
• Mitochondrial Ca2+ channels: Great unknowns with important functions

  2010cited by this paper
• MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake

  2010cited by this paper
• Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels.

  2010cited by this paper
• The contribution of UCP2 and UCP3 to mitochondrial Ca(2+) uptake is differentially determined by the source of supplied Ca(2+).

  2010cited by this paper
• Uncoupling protein 3 adjusts mitochondrial Ca2+ uptake to high and low Ca2+ signals

  2010cited by this paper
• Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca2+/H+ Antiporter

  2009cited by this paper
• Mitochondria: the hub of cellular Ca2+ signaling.

  2008cited by this paper
• UCP2/3 — likely to be fundamental for mitochondrial Ca2+ uniport

  2008cited by this paper
• Mitochondria and calcium in health and disease.

  2008cited by this paper
• Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport

  2007cited by this paper
• Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs.

  2007cited by this paper
• A New Type of Non-Ca2+-buffering Apo(a)-based Fluorescent Indicator for Intraluminal Ca2+ in the Endoplasmic Reticulum*

  2006cited by this paper
• Survival

  2004cited by this paper
• The Wellcome Prize Lecture

  2003cited by this paper
• Store-operated Ca2+ entry: dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.

  2003cited by this paper
• Cytoplasmic Ca2+ at low submicromolar concentration stimulates mitochondrial metabolism in rat luteal cells

  2001cited by this paper
• A model for receptor-regulated calcium entry.

  1986cited by this paper

• MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU

  2025cites this paper
• A quad-cistronic fluorescent biosensor system for real-time detection of subcellular Ca2+ signals.

  2025cites this paper
• Role of Mitochondrial Calcium Dysregulation in Alzheimer’s Disease Pathogenesis

  2025cites this paper
• Annexin A5 controls VDAC1-dependent mitochondrial Ca2+ homeostasis and determines cellular susceptibility to apoptosis

  2025influential citation
• Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.

  2024cites this paper
• Implications of mitochondrial membrane potential gradients on signaling and ATP production analyzed by correlative multi-parameter microscopy

  2024cites this paper
• Calcium signaling in mitochondrial intermembrane space.

  2024cites this paper
• Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease

  2024cites this paper
• MICU1 deficiency alters mitochondrial morphology and cytochrome C release.

  2023cites this paper
• Synergy of uncoupling proteins (1 and 2) with mitochondrial Ca2+ uptake machinery potentiate mitochondrial uncoupling.

  2023cites this paper
• Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell

  2022cites this paper
• Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ homeostasis

  2022cites this paper
• An unexpected effect of risperidone reveals a nonlinear relationship between cytosolic Ca2+ and mitochondrial Ca2+ uptake.

  2022cites this paper
• MICU1 controls spatial membrane potential gradients and guides Ca2+ fluxes within mitochondrial substructures

  2022cites this paper
• Mitochondrial Ca2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

  2022cites this paper
• Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ homeostasis

  2022cites this paper
• Mitochondrial Calcium Uniporter Affects Neutrophil Bactericidal Activity during Staphylococcus aureus Infection

  2021cites this paper
• Mitochondrial calcium exchange in physiology and disease.

  2021cites this paper
• Modeling the Effects of Calcium Overload on Mitochondrial Ultrastructural Remodeling

  2021cites this paper
• Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.

  2021cites this paper
• HSF1 and Molecular Chaperones in Biology and Cancer

  2020cites this paper
• Structure of the MICU1–MICU2 heterodimer provides insights into the gatekeeping threshold shift

  2020cites this paper
• Molecular Nature and Physiological Role of the Mitochondrial Calcium Uniporter Channel.

  2020cites this paper
• Mitochondrial Ca2+ in heart failure: Not enough or too much?

  2020cites this paper
• The contribution of uncoupling protein 2 to mitochondrial Ca2+ homeostasis - a short revisit.

  2020cites this paper
• The Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism

  2020cites this paper
• The Impact of the ER Unfolded Protein Response on Cancer Initiation and Progression: Therapeutic Implications.

  2020cites this paper
• The Concept of Calcium Signature and Its Involvement in Other Signaling Pathways

  2020cites this paper
• Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+

  2019cites this paper
• Role of mitochondrial Ca2+ homeostasis in cardiac muscles.

  2019cites this paper
• The EF-Hand Protein CALML6 Suppresses Antiviral Innate Immunity by Impairing IRF3 Dimerization.

  2019cites this paper
• MICU1 controls cristae junction and spatially anchors mitochondrial Ca2+ uniporter complex

  2019cites this paper
• Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer’s disease

  2019cites this paper
• Development and Application of Sub-Mitochondrial Targeted Ca2 + Biosensors

  2019cites this paper
• Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy

  2019cites this paper
• Single-Cell Investigation of Endothelial Nitric Oxide Dynamics

  2018influential citation
• Molecular mechanisms and functions of mitochondrial calcium transport in neurons

  2018cites this paper
• Akt‐mediated phosphorylation of MICU1 regulates mitochondrial Ca2+ levels and tumor growth

  2018cites this paper
• Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

  2018cites this paper
• Through modulation of cardiac Ca2+ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+‐mediated arrhythmias

  2017cites this paper
• Microcalorimetric investigation of six alkaloids from Radix Aconite Lateralis Preparata (Fuzi) on the metabolic activity of mitochondria isolated from rat liver

  2017cites this paper
• Mechanistic investigations into pro-survival and pro-death neuronal Ca2+ signalling pathways

  2017cites this paper
• High‐affinity cooperative Ca2+ binding by MICU1–MICU2 serves as an on–off switch for the uniporter

  2017cites this paper
• Intact mitochondrial Ca2+ uniport is essential for agonist‐induced activation of endothelial nitric oxide synthase (eNOS)

  2017cites this paper
• The Role of Mitochondria in the Activation/Maintenance of SOCE: The Contribution of Mitochondrial Ca2+ Uptake, Mitochondrial Motility, and Location to Store-Operated Ca2+ Entry.

  2017cites this paper
• The Role of Mitochondria in the Activation/Maintenance of SOCE: Store-Operated Ca2+ Entry and Mitochondria.

  2017cites this paper
• Expression of MICU1 after experimental focal cerebral ischemia in adult rats

  2017cites this paper
• Molecular Players of Mitochondrial Calcium Signaling: Similarities and Different Aspects in Various Organisms

  2017cites this paper
• DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter

  2017cites this paper
• The Roles of Mitochondrial Cation Channels Under Physiological Conditions and in Cancer.

  2017cites this paper
• The mitochondrial Ca2+ uniporter: regulation by auxiliary subunits and signal transduction pathways.

  2016cites this paper
• Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca2+ Coupling Between the Greatly Tethered Endoplasmic Reticulum and Mitochondria

  2016cites this paper
• PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca2+ uptake in immortalized cells

  2016cites this paper
• Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex

  2016cites this paper
• Regulation of mitochondrial calcium in plants versus animals.

  2016cites this paper
• Wide-field microscopic FRET imaging using simultaneous spectral unmixing of excitation and emission spectra.

  2016cites this paper
• The mitochondrial Ca uniporter: regulation by auxiliary subunits and signal transduction pathways

  2016cites this paper
• Expression and preliminary characterization of human MICU2

  2016cites this paper
• The mitochondrial Ca 2 + uniporter : Regulation by auxiliary subunits and signal 1 transduction pathways 2 3

  2016influential citation
• PRMT 1-mediated methylation of MICU 1 is a key for the engagement of UCP 2 in mitochondrial Ca

  2016influential citation
• Annexin-A5 is fundamental for VDAC1-dependent mitochondrial Ca2+ homeostasis and determines the susceptibility to apoptosis.

  year unknowncites this paper