The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance

Abstract

Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.

Keywords: in vivo models; mitochondria; optic atrophy; retinal ganglion cells (RGC); retinal organoids.

FIGURE 1

Unmyelinated axons within the optic nerve are associated with a greater mitochondrial load. The axons of the RGCs are unmyelinated within the retina, an adaptation which likely exists to prevent myelin from impeding light reaching the photoreceptors. Myelination initiates following the lamina cribrosa, a network of collagen fibers in the optic nerve head approximately 400 μm thick the RGC axons traverse to pass through the sclera. The unmyelinated region is associated with a higher density of mitochondria than the adjacent myelinated sections. This unique architecture of the RGCs is a possible explanation as to why the optic nerve appears so vulnerable to degeneration associated with mitochondrial dysfunction.

FIGURE 2

Mitochondrial localization and function of autosomal OA genes. Schematic demonstrating the localization and function of proteins encoded by autosomal OA-associated genes. The localization of proteins encoded by autosomal OA-associated genes within and in association with the mitochondria emphasizes the relevance of these organelles to autosomal OA. WFS1 is localized to the ER, but is enriched at MAMs. DNM1L is recruited from the cytoplasm to the OMM to facilitate mitochondrial fission. There is conflicting evidence as to whether OPA3 is localized to the IMM or OMM.