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

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, Nana Gogichaishvili, Merle Mandel, Mario Plaas, Eero Vasar, Jens Loncke, Tim Vervliet, Ting-Fen Tsai, Geert Bultynck, Vladimir Veksler and Allen Kaasik ()
Additional contact information
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
Zuzana Hodurova: University of Tartu
Michal Cagalinec: University of Tartu
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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50502-x

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