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ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome

Author

Listed:
  • Mailis Liiv

    (University of Tartu)

  • Annika Vaarmann

    (University of Tartu)

  • Dzhamilja Safiulina

    (University of Tartu)

  • Vinay Choubey

    (University of Tartu)

  • Ruby Gupta

    (University of Tartu)

  • Malle Kuum

    (University of Tartu)

  • Lucia Janickova

    (University of Tartu
    University of Fribourg
    Institute of Experimental Pharmacology and Toxicology)

  • Zuzana Hodurova

    (University of Tartu
    Institute of Experimental Pharmacology and Toxicology)

  • Michal Cagalinec

    (University of Tartu
    Slovak Academy of Sciences)

  • Akbar Zeb

    (University of Tartu)

  • Miriam A. Hickey

    (University of Tartu)

  • Yi-Long Huang

    (Peitou)

  • Nana Gogichaishvili

    (University of Tartu)

  • Merle Mandel

    (University of Tartu)

  • Mario Plaas

    (University of Tartu)

  • Eero Vasar

    (University of Tartu)

  • Jens Loncke

    (Department of Cellular and Molecular Medicine)

  • Tim Vervliet

    (Department of Cellular and Molecular Medicine)

  • Ting-Fen Tsai

    (Peitou)

  • Geert Bultynck

    (Department of Cellular and Molecular Medicine)

  • Vladimir Veksler

    (Inserm)

  • Allen Kaasik

    (University of Tartu)

Abstract

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.

Suggested Citation

  • Mailis Liiv & Annika Vaarmann & Dzhamilja Safiulina & Vinay Choubey & Ruby Gupta & Malle Kuum & Lucia Janickova & Zuzana Hodurova & Michal Cagalinec & Akbar Zeb & Miriam A. Hickey & Yi-Long Huang & Na, 2024. "ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50502-x
    DOI: 10.1038/s41467-024-50502-x
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    References listed on IDEAS

    as
    1. Maurizio Delvecchio & Matteo Iacoviello & Antonino Pantaleo & Nicoletta Resta, 2021. "Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype–Phenotype Correlations," IJERPH, MDPI, vol. 18(9), pages 1-12, April.
    2. Adam Bartok & David Weaver & Tünde Golenár & Zuzana Nichtova & Máté Katona & Száva Bánsághi & Kamil J. Alzayady & V. Kaye Thomas & Hideaki Ando & Katsuhiko Mikoshiba & Suresh K. Joseph & David I. Yule, 2019. "IP3 receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Mathew Tantama & Juan Ramón Martínez-François & Rebecca Mongeon & Gary Yellen, 2013. "Imaging energy status in live cells with a fluorescent biosensor of the intracellular ATP-to-ADP ratio," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
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