One therapy to protect them all: Controlling diabetic eye disease in anterior and posterior segment via mitophagy‐activating drugs

Abstract

Aims/Purpose: The accumulation of dysfunctional mitochondria has been implicated in the pathogenesis of diabetic eye disease through the impairment of mitochondrial quality control (MQC). This study aimed to investigate whether mitophagy‐activating drugs can alleviate pathology in the anterior and posterior ocular tissues of type‐1 diabetic mice.Methods: Mitophagy was evaluated in corneal and retinal tissues from diabetic mitophagy reporter mice (mitoQC‐Ins2Akita). The therapeutic potential of targeting mitophagy was evaluated by treating diabetic Ins2Akita mice with PIA‐01 (a PINK1‐independent mitophagy activator). Treatment was delivered orally between 4 and 8 months of diabetes. Ocular degenerative changes were evaluated by scotopic electroretinography (ERG), along with immunohistochemical analysis of retinal neurons and corneal cytoarchitecture.Results: Indicative of deteriorated MQC, mitophagy and mitochondrial transcription factor A (TFAM) positive mitochondrial nucleoids (which contain mtDNA) significantly decreased in the cornea and retina by 8 months of diabetes. Oral delivery of PIA‐01 restored TFAM+ mitochondrial nucleoids, leading to improved visual outcomes in Ins2Akita mice. In the retina, this was reflected by improved ERG responses (e.g. increased scotopic a‐wave and b‐wave amplitudes), while also protecting retinal neurons, including cone‐photoreceptors, synaptic structures, amacrine cells and retinal ganglion cells. This protection extended to the anterior segment, where PIA‐01 rescued corneal cytoarchitecture (basal epithelium and stroma) in diabetic mice.Conclusions: Diabetes progresses with deterioration of MQC in anterior and posterior ocular tissues. Rescuing MQC via mitophagy‐activating drugs may allow for multisystem therapies to control diabetic eye disease.