LETM1-Mediated K+ and Na+ Homeostasis Regulates Mitochondrial Ca2+ Efflux

Ca2+ transport across the inner membrane of mitochondria (IMM) is of major importance for their functions in bioenergetics, cell death and signaling. It is therefore tightly regulated. It has been recently proposed that LETM1—an IMM protein with a crucial role in mitochondrial K+/H+ exchange and volume homeostasis—also acts as a Ca2+/H+ exchanger. Here we show for the first time that lowering LETM1 gene expression by shRNA hampers mitochondrial K+/H+ and Na+/H+ exchange. Decreased exchange activity resulted in matrix K+ accumulation in these mitochondria. Furthermore, LETM1 depletion selectively decreased Na+/Ca2+ exchange mediated by NCLX, as observed in the presence of ruthenium red, a blocker of the Mitochondrial Ca2+ Uniporter (MCU). These data confirm a key role of LETM1 in monovalent cation homeostasis, and suggest that the effects of its modulation on mitochondrial transmembrane Ca2+ fluxes may reflect those on Na+/H+ exchange activity.

• Publication year

  2017

• Venue

  Frontiers in Physiology

• Publication date

  2017-11-17

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3389/fphys.2017.00839PMID 29204122PMCID 5698270
• 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.

• Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase

  2019cited by this paper
• Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter

  2016cited by this paper
• Enjoy the Trip: Calcium in Mitochondria Back and Forth.

  2016cited by this paper
• Mg2+ differentially regulates two modes of mitochondrial Ca2+ uptake in isolated cardiac mitochondria: implications for mitochondrial Ca2+ sequestration

  2016cited by this paper
• The molecular era of the mitochondrial calcium uniporter

  2015influential reference
• Gene essentiality and synthetic lethality in haploid human cells

  2015cited by this paper
• Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy

  2015influential reference
• Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1

  2014influential reference
• LETM1‐dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation

  2014influential reference
• LETM1 in mitochondrial cation transport

  2014cited by this paper
• LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition

  2014cited by this paper
• NCLX Protein, but Not LETM1, Mediates Mitochondrial Ca2+ Extrusion, Thereby Limiting Ca2+-induced NAD(P)H Production and Modulating Matrix Redox State*

  2014influential reference
• Trypanosome Letm1 Protein Is Essential for Mitochondrial Potassium Homeostasis*

  2013influential reference
• Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf–Hirschhorn syndrome

  2013influential reference
• Dynamic buffering of mitochondrial Ca2+ during Ca2+ uptake and Na+-induced Ca2+ release

  2013cited by this paper
• Faculty Opinions recommendation of A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.

  2011cited by this paper
• Integrative genomics identifies MCU as an essential component of 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
• Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. 1966.

  2011cited by this paper
• NCLX is an essential component of mitochondrial Na+/Ca2+ exchange

  2009cited by this paper
• Genome-Wide RNAi Screen Identifies Letm1 as a Mitochondrial Ca2+/H+ Antiporter

  2009influential reference
• Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts

  2007cited by this paper
• Electroneutral K+/H+ exchange in mitochondrial membrane vesicles involves Yol027/Letm1 proteins.

  2005cited by this paper
• The LETM1/YOL027 Gene Family Encodes a Factor of the Mitochondrial K+ Homeostasis with a Potential Role in the Wolf-Hirschhorn Syndrome*

  2004influential reference
• Mitochondrial transport of cations: channels, exchangers, and permeability transition.

  1999cited by this paper
• On the regulation of Na+/H+ and K+/H+ antiport in yeast mitochondria: evidence for the absence of an Na(+)-selective Na+/H+ antiporter.

  1993cited by this paper
• Purification of a reconstitutively active K+/H+ antiporter from rat liver mitochondria.

  1990cited by this paper
• Lithium Ion is a Competitive Inhibitor of the Na+ Selective Na+/H+ Antiporter from Mitochondria

  1988influential reference
• Mitochondrial Volume Control

  1988cited by this paper
• Sodium/proton antiporters in the mitochondrial inner membrane.

  1988cited by this paper
• Ca2+ as a second messenger within mitochondria

  1986influential reference
• On the mechanism by which dicyclohexylcarbodiimide and quinine inhibit K+ transport in rat liver mitochondria.

  1986influential reference
• K+/H+ antiport in heart mitochondria.

  1984cited by this paper
• Electroneutral H+-K+ exchange in liver mitochondria. Regulation by membrane potential.

  1983cited by this paper
• Quinine inhibition of Na+ and K+ transport provides evidence for two cation/H+ exchangers in rat liver mitochondria.

  1982influential reference
• The calcium cycle of mitochondria

  1979cited by this paper
• The release of calcium from heart mitochondria by sodium.

  1974cited by this paper
• Translocation of some anions cations and acids in rat liver mitochondria.

  1969cited by this paper
• CHEMIOSMOTIC COUPLING IN OXIDATIVE AND PHOTOSYNTHETIC PHOSPHORYLATION

  1966cited by this paper

• Decoding mitochondrial signaling: neutrophil-tumor cell crosstalk in orchestrating cancer progression.

  2026cites this paper
• An ArfGAP-dependent signaling modulates synaptic plasticity via IP3-regulated calcium release from the endoplasmic reticulum

  2026cites this paper
• LETM1 and Mitochondrial Calcium Homeostasis: A Controversial but Critical Role in Cellular Function and Disease

  2025cites this paper
• The central role of Na+ in mitochondrial bioenergetics, ROS production and homeostasis.

  2025cites this paper
• Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation

  2025cites this paper
• The apo LETM1 F‐EF‐hand adopts a closed conformation that underlies a multi‐modal sensory role in mitochondria

  2025cites this paper
• The roles of mitochondria in global and local intracellular calcium signalling

  2025cites this paper
• Mitochondrial ATP-Sensitive K+ Channels (MitoKATP) Regulate Brown Adipocyte Differentiation and Metabolism

  2025cites this paper
• Decoding the influence of mitochondrial Ca2+ regulation on neurodegenerative disease progression

  2025cites this paper
• Current Challenges and Future Directions in Mitochondrial Potassium Transport Research

  2025cites this paper
• Mitochondrial Calcium Signaling in Hepatocyte Health and Disease.

  2025cites this paper
• An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium.

  2024cites this paper
• Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species

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

  2024cites this paper
• Post-translational modifications and protein quality control of mitochondrial channels and transporters

  2023cites this paper
• Patch-clamp technique to study mitochondrial membrane biophysics

  2023cites this paper
• Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology

  2023cites this paper
• Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart

  2023cites this paper
• Comparative analysis of wild-type and chloroplast MCU-deficient plants reveals multiple consequences of chloroplast calcium handling under drought stress

  2023cites this paper
• Mitochondrial Calcium: Effects of Its Imbalance in Disease

  2022cites this paper
• TMBIM5 is the Ca2+/H+ antiporter of mammalian mitochondria

  2022influential citation
• The mitochondrial sodium/calcium exchanger NCLX (Slc8b1) in B lymphocytes.

  2022cites this paper
• Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

  2022cites this paper
• Determinants, Maintenance and Function of Organellar pH.

  2022cites this paper
• TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy

  2022influential citation
• Ca2+ Dyshomeostasis Links Risk Factors to Neurodegeneration in Parkinson’s Disease

  2022cites this paper
• The cation exchanger Letm1, circadian rhythms, and NAD(H) levels interconnect in diurnal zebrafish

  2022cites this paper
• Routes for Potassium Ions across Mitochondrial Membranes: A Biophysical Point of View with Special Focus on the ATP-Sensitive K+ Channel

  2021cites this paper
• Mitochondrial osmoregulation in evolution, cation transport and metabolism.

  2021cites this paper
• The leucine zipper EF‐hand containing transmembrane protein‐1 EF‐hand is a tripartite calcium, temperature, and pH sensor

  2021cites this paper
• Mitochondrial Calcium Signaling in Pancreatic β-Cell

  2021cites this paper
• LETM1: A Single Entity With Diverse Impact on Mitochondrial Metabolism and Cellular Signaling

  2021cites this paper
• Mitochondrial calcium at the synapse.

  2021cites this paper
• Mitochondrial K+ channels and their implications for disease mechanisms.

  2021cites this paper
• Calcium transport systems in chloroplasts and mitochondria of plant cells

  2021cites this paper
• Evaluation of Mitochondrial Function and Morphology in Drosophila.

  2021cites this paper
• Chlamydomonas reinhardtii cellular compartments and their contribution to intracellular calcium signalling

  2021cites this paper
• Actin-related protein 4: an unconventional negative regulator of mitochondrial calcium in protozoan parasite Leishmania.

  2021cites this paper
• Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

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

  2021cites this paper
• Computational modeling of mitochondrial K+- and H+-driven ATP synthesis.

  2021cites this paper
• Mitochondrial calcium : mechanisms of transport , regulation and 1 cellular functions [ Au : OK ? Or ‘ Mitochondrial calcium : 2 machineries , regulation and cellular functions ’ ? ]

  2021cites this paper
• Molecular machinery regulating mitochondrial calcium levels: The nuts and bolts of mitochondrial calcium dynamics.

  2020influential citation
• Channels and transporters for inorganic ions in plant mitochondria: Prediction and facts

  2020cites this paper
• Total Matrix Ca2+ Modulates Ca2+ Efflux via the Ca2+/H+ Exchanger in Cardiac Mitochondria

  2020cites this paper
• Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD

  2020cites this paper
• Ca2+ Fluxes and Cancer.

  2020cites this paper
• Mitochondrial Ion Channels and Transporters in Plants: Prediction and Facts.

  2020cites this paper
• Manganese-induced mitochondrial dysfunction is not detectable at exposures below the acute cytotoxic threshold in neuronal cell types.

  2020cites this paper
• The mitochondrial inner membrane protein LETM1 modulates cristae organization through its LETM domain

  2020cites this paper
• Imaging Mitochondrial Functions: From Fluorescent Dyes to Genetically-Encoded Sensors

  2020cites this paper
• Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship.

  2019cites this paper
• Tracking intra‐ and inter‐organelle signaling of mitochondria

  2019cites this paper
• Roles for intracellular cation transporters in respiratory growth of yeast.

  2019cites this paper
• CO2 promotes the conjugative transfer of multiresistance genes by facilitating cellular contact and plasmid transfer.

  2019cites this paper
• LETM1: Essential for Mitochondrial Biology and Cation Homeostasis?

  2019cites this paper
• Mitochondria as Signaling Platforms

  2019cites this paper
• Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

  2019cites this paper
• Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer (Review).

  2019influential citation
• Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase

  2019cites this paper
• Molecular Mechanisms of Leucine Zipper EF-Hand Containing Transmembrane Protein-1 Function in Health and Disease

  2019cites this paper
• Identification and characterization of Letm1 gene in Toxoplasma gondii

  2018cites this paper
• The Influence of MicroRNAs on Mitochondrial Calcium

  2018cites this paper
• Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

  2018cites this paper
• The contribution of organelles to plant intracellular calcium signalling

  2018cites this paper
• The machineries, regulation and cellular functions of mitochondrial calcium

  2018cites this paper
• Molecular mechanisms and functions of mitochondrial calcium transport in neurons

  2018cites this paper
• Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system leading to a clinical spectrum with predominant nervous system involvement

  year unknowncites this paper
• Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system leading to a clinical spectrum with predominant nervous system involvement

  year unknowncites this paper