Physalin A protects against diabetes-like retinal neurodegeneration via autophagy, mitophagy, and antioxidant pathways in Drosophila melanogaster

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Background: Diabetic retinopathy begins with neuroretinal dysfunction driven by oxidative stress, mitochondrial injury, and impaired proteostasis before microvascular pathology emerges. Drosophila provides a tractable neuron-centric model to interrogate these early events. Physalin A (PA), a withanolide, has antioxidative and anti-inflammatory activities, yet its retina-specific mitochondrial actions in vivo remain incompletely defined. Purpose: To determine whether PA rescues visual function and neuronal integrity in insulin receptor mutant Drosophila with DR-like retinal injury, and to delineate associated pathways in autophagy, mitophagy, and antioxidant defense. Methods: Adult w1118; P{GMR-InR.A1325D}3 Drosophila received dietary PA (6–24 μM) for seven days. Visual function was quantified by electroretinography and phototaxis. Retinal structure was assessed by histology, scanning electron microscopy, and confocal imaging. Autophagy, mitophagy, and apoptosis were profiled by Western blot, immunofluorescence, cathepsin B/L activity, and qPCR targeting PINK1/parkin, mTOR/Rheb, and antioxidant genes. Transmission electron microscopy evaluated mitochondrial morphology and autophagosome abundance. ATP content and oxidative phosphorylation complex activities were measured biochemically. Results: PA restored electroretinographic amplitudes and off-transients and slowed the decline in phototaxis without altering glycemia or body weight. PA preserved ommatidial architecture, increased retinal thickness, and normalized photoreceptor organization. Molecularly, PA increased LC3B-II with p62 reduction, suppressed cytochrome c release and cleaved caspase-3, and upregulated PINK1/parkin while down-modulating mTOR/Rheb. Antioxidant transcripts, including SOD1/2/3, catalase, and Prx2, were elevated. Ultrastructurally, mitochondria exhibited restored cristae and reduced swelling, with increased autophagosomes. Functionally, ATP levels and oxidative phosphorylation complex I–V activities were rescued toward wild-type ranges, aligning improved bioenergetics with enhanced mitochondrial quality control. Conclusion: PA confers neuroretinal protection in DR-like Drosophila by rebalancing apoptosis and autophagy, activating PINK1/parkin-mediated mitophagy, and strengthening antioxidant defenses, culminating in structural preservation and recovery of visual function. These findings support a mitochondria-centered mechanism for PA and nominate it as a candidate for early intervention targeting neurodegenerative phase of DR

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