Apoptosis inducing factor deficiency causes retinal photoreceptor degeneration. The protective role of the redox compound methylene blue

Dysfunction in mitochondrial oxidative phosphorylation (OXPHOS) underlies a wide spectrum of human ailments known as mitochondrial diseases. Deficiencies in complex I of the electron transport chain (ETC) contribute to 30–40% of all cases of mitochondrial diseases, and leads to eye disease including optic nerve atrophy and retinal degeneration. The mechanisms responsible for organ damage in mitochondrial defects may include energy deficit, oxidative stress, and an increase in the NADH/NAD+ redox ratio due to decreased NAD+ regeneration. Currently, there is no effective treatment to alleviate human disease induced by complex I defect. Photoreceptor cells have the highest energy demand and dependence on OXPHOS for survival, and the lowest reserve capacity indicating that they are sensitive to OXPHOS defects. We investigated the effect of mitochondrial OXPHOS deficiency on retinal photoreceptors in a model of mitochondrial complex I defect (apoptosis inducing factor, AIF-deficient mice, Harlequin mice), and tested the protective effect of a mitochondrial redox compound (methylene blue, MB) on mitochondrial and photoreceptor integrity. MB prevented the reduction in the retinal thickness and protein markers for photoreceptor outer segments, Muller and ganglion cells, and altered mitochondrial integrity and function induced by AIF deficiency. In rotenone-induced complex I deficient 661 W cells (an immortalized mouse photoreceptor cell line) MB decreased the NADH/NAD+ ratio and oxidative stress without correcting the energy deficit, and improved cell survival. MB deactivated the mitochondrial stress response pathways, the unfolding protein response and mitophagy. In conclusion, preserving mitochondrial structure and function alleviates retinal photoreceptor degeneration in mitochondrial complex I defect.
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Highlights • Mitochondrial complex I causes damage of the retinal photoreceptor cells and their outer segments. • Methylene blue decreases the NADH/ NAD+ ratio and oxidative stress induced by complex I defect. • Methylene blue deactivates the mitochondrial stress response pathways. • Methylene blue maintains mitochondrial integrity and function. • Methylene blue improves photoreceptor cell survival and outer segment integrity.