8th International Wolfram Symposium Presentation Liiv M1, Vaarmann A1, Kuum M1, Gupta-Blixt R1, Janickova L1, Hodurova Z1, Cagalinec M1, Zeb A1, Choubey V1, Hickey MA1, Safiulina D1, Yi-Long H2, Gogichaisvili N1, Mandel M1, Plaas M1, Vasar E1, Loncke J3, Vervliet T3, Tsai T-F2, Bultynck G3, Veksler V4, Kaasik A1.1Departments of Pharmacology and Physiology, University of Tartu, Estonia. 2Department of Life Sciences, National Yang Ming Chiao Tung University, Taiwan 3Laboratory of Molecular and Cellular Signaling, KU Leuven, Belgium. 4INSERM UMR-S 1180, University Paris-Saclay, France.

Abstract: Wolfram syndrome (WS) is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in WS involves poor endoplasmic reticulum (ER) Ca2+ handling, but how this disturbance leads to the disease is not known. Although the clinical symptoms of WS resemble mitochondrial diseases and WFS1 or CISD2 deficiency leads to mitochondrial abnormalities, no causal link has been established between the ER defects, mitochondrial dysfunction and cell metabolic disturbances. The current study, performed in primary isolated neurons, the most affected and disease-relevant cells, involving both WS genes explains how the disturbed ER Ca2+ handling compromises mitochondrial function and in turn affects neuronal health. Loss of ER Ca2+ content in the axons of the WFS1 or CISD2 deficient neurons is associated with lower IP3R3-mediated Ca2+ transfer from ER to mitochondria leading to decreased mitochondrial Ca2+ uptake. In turn, reduction in mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased axoplasmic NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress further compromise the neurons health. Our work also identifies pharmacological targets and compounds that potentially may restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal function.