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⁺

SUBMITTER: Liiv M 

PROVIDER: S-EPMC11271478 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature