ArticleThe Journal of biological chemistry2014
NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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73 citing papers in PubMed, 112 citations in OpenAlex.
- Molecular mechanisms of mitochondrial CaNature communications · 2026Article
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- Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.Acta neuropathologica communications · 2026Article
- Molecular mechanisms of mitochondrial CabioRxiv : the preprint server for biology · 2026Article
- Intracellular Calcium as a Regulator of Polarization and Target Reprogramming of Macrophages.International journal of molecular sciences · 2025Review
- Mitochondrial CaJournal of cellular physiology · 2025Review
- The roles of mitochondria in global and local intracellular calcium signalling.Nature reviews. Molecular cell biology · 2025Review
- Crosstalk between calcium and reactive oxygen species signaling in cancer revisited.Cell calcium · 2025Review
- Roles of calcium in ameloblasts during tooth development: A scoping review.Journal of Taibah University Medical Sciences · 2025Review
- The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.Autophagy reports · 2025Article
- Dihydroartemisinin inhibits ATP6 activity, reduces energy metabolism of hepatocellular carcinoma cells, promotes apoptosis and inhibits metastasis via CANX.Oncology letters · 2024Article
- Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.Aging and disease · 2024Review
- NLRP14 Safeguards Calcium Homeostasis via Regulating the K27 Ubiquitination of Nclx in Oocyte-to-Embryo Transition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.Antioxidants (Basel, Switzerland) · 2023Review
- Sexual dimorphism in bidirectional SR-mitochondria crosstalk in ventricular cardiomyocytes.Basic research in cardiology · 2023Article
- Calcium and Reactive Oxygen Species Signaling Interplays in Cardiac Physiology and Pathologies.Antioxidants (Basel, Switzerland) · 2023Review
- Evolutionary View on Lactate-Dependent Mechanisms of Maintaining Cancer Cell Stemness and Reprimitivization.Cancers · 2022Review
- MicroRNAs as Regulators of Cancer Cell Energy Metabolism.Journal of personalized medicine · 2022Review
- Mitochondrial calcium exchange in physiology and disease.Physiological reviews · 2022Review
- Mitochondria in neurodegeneration.Current opinion in physiology · 2022Article
13 more citing papers are in PubMed but not listed here.
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6 authors at 2 institutions in 1 country.
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Abstract
Mitochondria capture and subsequently release Ca(2+) ions, thereby sensing and shaping cellular Ca(2+) signals. The Ca(2+) uniporter MCU mediates Ca(2+) uptake, whereas NCLX (mitochondrial Na/Ca exchanger) and LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) were proposed to exchange Ca(2+) against Na(+) or H(+), respectively. Here we study the role of these ion exchangers in mitochondrial Ca(2+) extrusion and in Ca(2+)-metabolic coupling. Both NCLX and LETM1 proteins were expressed in HeLa cells mitochondria. The rate of mitochondrial Ca(2+) efflux, measured with a genetically encoded indicator during agonist stimulations, increased with the amplitude of mitochondrial Ca(2+) ([Ca(2+)]mt) elevations. NCLX overexpression enhanced the rates of Ca(2+) efflux, whereas increasing LETM1 levels had no impact on Ca(2+) extrusion. The fluorescence of the redox-sensitive probe roGFP increased during [Ca(2+)]mt elevations, indicating a net reduction of the matrix. This redox response was abolished by NCLX overexpression and restored by the Na(+)/Ca(2+) exchanger inhibitor CGP37157. The [Ca(2+)]mt elevations were associated with increases in the autofluorescence of NAD(P)H, whose amplitude was strongly reduced by NCLX overexpression, an effect reverted by Na(+)/Ca(2+) exchange inhibition. We conclude that NCLX, but not LETM1, mediates Ca(2+) extrusion from mitochondria. By controlling the duration of matrix Ca(2+) elevations, NCLX contributes to the regulation of NAD(P)H production and to the conversion of Ca(2+) signals into redox changes.
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