Mitochondrial Transplantation as a Novel Therapeutic for Retinal Metabolic Dysfunction‐Driven Disease

Abstract

Metabolic dysfunction and mitochondria defect are implicated in several age‐associated diseases including age‐related macular degeneration (AMD), a leading cause of blindness in the elderly. In AMD, mitochondrial oxidative stress in the retinal pigment epithelium (RPE) drives disease progression and growth of atrophic lesions. Mitochondria release and uptake has been recently identified as a novel mechanism of intercellular communication but its implication in ocular diseases such as AMD has never been investigated. Here, we examined the role of mitochondrial transfer as a new mechanism of metabolic crosstalk between RPE cells. Diseased mitochondria were purified from RPE cells treated with the AMD‐associated cytokine TNFα (10 ng/mL), administered to host RPE cells and the effects of MitoTNFA compared to MitoCtrl, isolated from control RPE, or exposure to exogenous TNFα. We showed that treatment of healthy RPE with MitoTNFA, and not MitoCtrl, triggers mitochondrial network fragmentation and transcriptional upregulation of inflammatory factors RelB, IL6, IL8, and repression of PGC1α, mirroring the effect of direct TNFα treatment. ELISA assay confirmed that the effects observed were not caused by presence of soluble TNFα within the mitochondrial fraction. Metabolic profiling using the Seahorse XFe96 bioanalyzer further validated the ability of MitoTNFA to phenocopy TNFα‐induced metabolic reprograming in RPE. Finally, we demonstrated that transfer of MitoCtrl improved the bioenergetic functions of both healthy and diseased RPE with significant increases in basal, maximal, and spare respiratory functions. Our results showed that mitochondria transfer recapitulates the context‐specific phenotype from donor to host cells in RPE. This new paradigm in RPE biology may not only explain the centrifugal expansion of RPE lesions in AMD but also presents a promising therapeutic avenue for mitochondria‐driven disorders such as AMD.