Abstract

Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited mitochondrial disorder characterised by painless, progressive, and sequential visual failure. Most cases of LHON are driven by mitochondrial DNA mutations which cause dysfunction of respiratory Complex I, triggering retinal ganglion cell loss. Retinal ganglion cell degeneration in LHON is thought to be linked to reduced production of metabolic intermediates and adenosine triphosphate, and enhanced reactive oxygen species production. Thus, decades of research have focussed on LHON as a disease of the retinal ganglion cells, which has considerably improved our understanding of the pathology but has yielded few therapeutic interventions. In addition, some LHON-associated phenomena remain unclear. In particular, we still do not fully understand the mechanisms underlying the recorded phenomenon of spontaneous visual recovery, in which patients experience measurable increases in visual acuity following onset of LHON vision loss. Understanding this phenomenon may be critical for developing new therapeutic approaches for LHON. Moreover, the contribution of non-neuronal cell populations to LHON pathology remains poorly understood despite a growing appreciation for the roles played by these cells in other neurodegenerative conditions. Astrocytes are a highly heterogeneous group of glial cells, found throughout the central nervous system including the retina and optic nerve, and are well-known for their role as key homeostatic mediators. In recent years, our appreciation for the role played by astrocytes in neurodegenerative diseases has expanded considerably, and we are now aware that astrocytes undergo significant loss of their homeostatic functions in neurodegenerative disease, acting as key mediators of neuronal loss. Importantly, the contributions astrocytes make toward mediating LHON pathology and visual recovery remain unclear, and provide promising ground for potentially novel therapeutic angles and enhanced understanding of this complex pathology. Here, we leverage human iPSC-derived astrocytes from patients with the LHON m.14484T>C genotype, to explore the role astrocytes play in LHON pathology, stratifying cells by their visual recovery status. We report that astrocytes undergo significant morphological and bioenergetic compromise in LHON, and that differences between 'recovery' and 'non-recovery' astrocytes may explain individual capacity for visual recovery, potentially opening novel therapeutic approaches.