Mitochondrial Transfer as a Novel Treatment for Metabolic Dysregulation Driven Disease of the Human Retina

Abstract

Age related macular degeneration (AMD) is a critical global illness which leads to degeneration of the ocular tissues and is a major cause of blindness in developed countries worldwide. Clinical and experimental evidence point to a specific tissue in the retina, namely the retinal pigment epithelium (RPE), as a key actor in the onset and progression of AMD (Atienzar-Aroca et al., 2018). RPE cells exert critical trophic functions for maintenance of visual function and RPE degeneration is associated with severe and often irreversible vision loss. In the context of AMD, disruption of normal metabolic function and oxidative damage to the RPE is thought to significantly contribute to the disease pathogenic process. Further insight to the underpinning mechanisms driving the alterations hallmark to AMD progression are evident in its unique patterning of RPE cell death, which suggest a neighbor crosstalk phenomenon may be occurring amongst adjacent cells. We postulate that one mechanism driving the centrifugal expansion of RPE degeneration and death in AMD is through mitochondrial transfer. First investigated in 1982, this mode of cellular communication has been reported in several tissues and implicated in a broad spectrum of disease. Conversely, driven from the reported ability to confer antibody resistance via exogenous mitochondrial incorporation in recipient cells in Shay and Clark’s seminal experiments, growing evidence suggests this mode of cell signaling may also hold potential as a therapeutic to revert cell pathophysiology. Despite these advances, description of the transformation potential and mechanisms via mitochondrial transplantation in the eye remains unknown. Here we performed a series of experiments to first demonstrate the effect of mitochondrial exchange on RPE homeostatic function through robust interrogation of the underpinning mechanisms that drive AMD pathogenesis. This was accomplished through quantitative, functional, and morphological evaluation of the effect of mitochondrion purified from normal and diseased RPE on normal RPE to mimic diseased conditions. Next, we investigated whether transfer of healthy mitochondria could restore normal function to diseased AMD-like cells. Taken together, these results demonstrate exogenous mitochondrial do incorporate into RPE and promote pathological change or metabolic recovery depending on their status, highlighting both a novel mechanism of AMD progression via mitochondrial exchange and a promising avenue to develop regenerative therapeutics for metabolic-driven diseases such as AMD.