Morphological Abnormalities of the Mitochondrial Network in Fibroblasts of Patients Affected With Autosomal Dominant and Recessive Optic Neuropathies

Abstract

Purpose:: Inherited non syndromic optic atrophies (OPA) are frequently inherited as an autosomal dominant trait. The most common of these autosomal dominant disorders are related to mutations in the OPA1 gene on chromosome 3q28. Two others uncommon loci have been reported on chromosome 18q12 (OPA4) and on chromosome 22q12.3 (OPA5), respectively. Besides, autosomal recessive non syndromic OPA are very rare. Until now, only one locus has been reported on chromosome 8q23 (ROA1). OPA1 and genes involved in syndromic forms of OA were shown to play a crucial role in the mitochondrial function. The purpose of this study was to investigate a possible involvement of mitochondria in autosomal dominant and recessive isolated OAs of unknown genetic origin by looking at the mitochondrial network.

Methods:: Fibroblasts of patients related to OPA1 (n=1), OPA5 (n = 2) and ROA1 (n=2) were labelled using MitoTracker Red CMXRos dye, a fluorescent mitochondrial marker that binds free sulfhydryls within the cells. Fibroblasts of age-matched controls were studied at the same time for each genetic subtype.

Results:: Morphological abnormalities of the mitochondrial network were observed in the five patients compared to the respective controls. The cellular distribution of mitochondria in fibroblasts of patients related to OPA5 (n=2) and OPA1 (n=1) was superimposable: the labelling of the MitoTracker Red CMXRos dye appeared fragmented and highly concentrated around the nucleus of cells (ring-like aspect). Interestingly, the distribution of mitochondria in the fibroblasts of the two patients related to ROA1 was also superimposable but clearly different from that of patients related to dominant optic atrophies. The labelling of the MitoTracker Red CMXRos dye was highly heterogeneous and testified a fragmentation of the mitochondrial network but no nuclear ring-like aspect was noted.

Conclusions:: This study suggests that a selective vulnerability of the optic nerve to perturbations in mitochondrial function may underlie a final common pathway in all inherited optic atrophies. These findings provide a rationale in order to select candidate genes as genes encoding proteins with high mitochondrial targeting probability for both the OPA5 and ROA1 loci.

Keywords: optic nerve • mitochondria • neuro-ophthalmology: optic nerve