ER Calcium Depletion as a Key Driver for Impaired ER-to-Mitochondria Calcium Transfer and Mitochondrial Dysfunction in Wolfram Syndrome

Abstract

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 ER Ca2+ handling, but how this disturbance leads to the disease is not known. 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 affects neuronal health. Loss of ER Ca2+ content in the axons of 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, reduction in mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased axoplasmic 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 function.