Disturbed interactions between mitochondria and the endoplasmic reticulum : implications for human disease

PhD ThesisInherited optic neuropathies cause significant visual impairment and this group of disorders affect at least 1 in 10,000 people in the United Kingdom. The pathological hallmark of inherited optic neuropathies is the preferential loss of retinal ganglion cells within the inner retina, which leads to optic nerve degeneration and subsequent visual failure. This thesis describes investigations into the underlying disease mechanisms of inherited optic neuropathies, including the potential involvement of mitochondrial dysfunction in the pathophysiology of Wolfram syndrome. A robustly phenotyped cohort of 30 optic atrophy patients with a likely genetic cause for their visual failure was screened for possible pathogenic mutations in the WFS1 (4p16.1), RTN4IP1 (6q21) and C12orf65 (12q24.31) genes. No pathogenic mutations were identified. Wolfram syndrome 1 (WFS1) is a rare genetic disease characterised by diabetes insipidus, diabetes mellitus, optic atrophy and deafness, and it is primarily caused by mutations in the WFS1 gene (4p16.1). A cell culture model consisting of fibroblasts derived from five patients harbouring confirmed recessive or dominant WFS1 mutations was used to explore the disease mechanisms of Wolfram syndrome. WFS1 mutations had a deleterious impact on calcium (Ca2+) transfer from the ER to the mitochondria, which was associated with impaired mitochondrial oxidative phosphorylation and differential sensitivity to the ER stressor thapsigargin. Wolfram syndrome 2 (WFS2) is caused by recessive mutations in the CISD2 gene (4q24) and shares many of the clinical features of WFS1. In CISD2-mutant fibroblasts, mitochondria-ER apposition was increased and there was evidence of disturbed Ca2+ homeostasis, including amplified Ca2+ transfer from the ER to mitochondria and raised cytosolic Ca2+. These results indicate that WFS1 and CISD2 mutations disturb cellular Ca2+ homeostasis and alter mitochondrial function supporting the hypothesis that mitochondrial dysfunction plays an important role in the neuropathology of Wolfram syndrome