Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenine confers neuroprotection regardless of glycaemic status.

Abstract

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while also imposing an extraordinary challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In Diabetic Retinopathy (DR) this therapeutic approach is further compounded by our lack of understanding of human retinal neurodegeneration, but also of how MQC processes interplay during disease progression. Here, we show for the first time that mitochondria remodel towards hyperfusion during retinal neurodegeneration in human and murine diabetes. Using Mito-QC reporter, we demonstrate that mitochondrial hyperfusion blunts the homeostatic turnover of mitochondria in diabetes, causing metabolic, neuronal, and neuro-inflammatory (glial) stress. By mimicking this mitochondrial remodelling in vitro, we also generated a drug discovery platform whereby glycosylated N6-furfuryladenine(s) (but not other PINK1-activators) restored mitochondrial turnover and cellular bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of glycosylated N6-furfuryladenine restored mitochondrial turnover in the murine (Ins2Akita) diabetic retina, improving clinical correlates (electroretinogram and SD-OCT) and conferring human-relevant neuroprotection regardless of glycaemic status. Collectively, our study provides new translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.