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

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.