PINK1‐mitophagy activator (PA‐01) overcomes mitochondrial hyperfusion conferring retinal neuroprotection in type‐1 diabetes

Abstract

Aims/Purpose: We hypothesize that exacerbated mitochondrial fusion abrogates mitophagy in diabetic retinopathy [DR]. Our aim was to rescue this process pharmacologically to prevent vision loss in a mouse model of type‐1 diabetes.Methods: We generated a drug screening platform mimicking mitochondrial hyperfusion in DR. To this end, retinal Müller cells (mouse primary and MIO‐M1 cell line) were antagonized for mitochondrial fission using a Drp1 inhibitor peptide under elevated glucose (30.5 mM) conditions. Pharmacological ‘hits’ rescuing mitophagy in conditions of diabetes‐induced hyperfusion were assessed for their capability to improve mitochondrial health (membrane potential [ΔΨm]) and bioenergetics (Seahorse). The bio‐activity of lead compounds were corroborated in vivo using diabetic mitophagy reporter mice (Mito‐QC Ins2Akita), while effectiveness to alleviate retinal degeneration was evaluated via electroretinography (ERG), retinal thickness (SD‐OCT) and morphometric analysis of retinal neurons.Results: Among all drugs screened, we identified PA‐01 (a PINK1‐mitophagy activator) as capable of safely rescuing mitophagy under conditions of diabetes‐induced mitochondrial hyperfusion. Accordingly, PA‐01 rescued mitochondrial health (ΔΨm) and bioenergetics in Müller glia cultures, by optimizing metabolic flux (basal‐ and ATP‐linked respiration). The bio‐activity of PA‐01 was demonstrated in vivo, where long‐term oral administration rescued mitochondrial hyperfusion and mitophagy in the diabetic retina, while further preventing neurodegeneration. This was reflected in i) improved scotopic ERG responses (increased a‐wave and b‐wave amplitudes), ii) improved SD‐OCT retinal thickness and iii) neuroprotection to photoreceptors, synaptic terminals and amacrine cells.Conclusions: Exacerbated mitochondrial fusion contributes to DR pathology by inhibiting mitophagy in Müller glia. Rescuing this process pharmacologically holds promising therapeutic potential to alleviate vision loss in DR.