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ziv rotfogel, Ortal Zaks, Maya Sharvit Bader, Arie Marcovich, Keren Ben Yaakov, Michal Simon, Hana Leiba; Therapeutic potential of mitochondrial transplantation in ocular diseases. Invest. Ophthalmol. Vis. Sci. 2020;61(7):317.
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© ARVO (1962-2015); The Authors (2016-present)
Mitochondrial dysfunction is associated with various incurable ocular diseases such as acute ischemic insults, age-related diseases like AMD and glaucoma and genetic mitochondrial diseases. Pharmacological therapeutic approaches targeted to the mitochondria have shown promising yet immature results. Here we propose to treat these pathologies by replacing the endogenous damaged mitochondria with exogenous healthy ones, by a novel modality known as mitochondrial transplantation (MitoPlant). In this modality, healthy mitochondria are extracted in-vitro, injected into dysfunctional tissue and are spontaneously internalized by the cells. MitoPlant was shown to facilitate functional recovery of tissues in mouse models of ischemic insults of the heart, liver and nervous system, and recently in pediatric patients with congenital heart disease. However, MitoPlant has never been shown in the eye, nor has been tested in pathologies other than ischemic insult. We hypothesize that MitoPlant in the eye may have a beneficial effect not only in acute ischemia but also in chronic and genetic ocular pathologies.
Mitochondria were isolated from human ARPE-19 cell-line and mouse livers, and their purity and function were evaluated. Mitochondrial uptake into several ocular-related cell lines was examined by flow cytometry, microscopy and PCR. MitoPlant protective effect against oxidative stress was examined in human corneal endothelial cells exposed to H2O2. Cell survival following MitoPlant was evaluated by Neutral Red assay. In-vivo mitochondrial uptake was demonstrated by intravitreal injection of freshly isolated mitochondria into C57BL/6 mice eye. Mitochondrial uptake by Retinal Ganglion Cells (RGCs) was determined 24 hours later by confocal microscopy and PCR. Retinas were assessed by Optical Coherence Tomography imaging system after 3 weeks.
We show that exogenous, functional mitochondria are spontaneously and effectively internalized by ocular cells in-vitro, and protect them from oxidative-stress induced death. Importantly, we show for the first time that injection of isolated mitochondria into the vitreous cavity of mice results in the internalization of functional mitochondria by the RGCs while maintaining normal structure of retinal layers.
Our results suggest that ocular transplantation of mitochondria may serve as a new therapeutic tool that can inhibit cell death in various ocular diseases.
This is a 2020 ARVO Annual Meeting abstract.
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