Humanin mitigates Aβ-induced RPE injury in AMD models via AMPK-Beclin1-dependent mitophagy activation

Age-related macular degeneration (AMD) is a leading cause of vision loss, characterized by drusen accumulation containing amyloid beta (Aβ). This Aβ induces oxidative stress, mitochondrial dysfunction, and degeneration in the retinal pigment epithelium (RPE), contributing to progressive vision loss. Current treatments for dry AMD are limited, highlighting the need for novel therapeutic strategies. Humanin (HN), a mitochondria-derived peptide, has demonstrated neuroprotective effects in Aβ-related neurodegenerative diseases, making it a promising candidate for AMD intervention by targeting mitochondrial health.

Researchers investigated Humanin's protective role in Aβ-induced retinal pathology using both in vivo and in vitro models. In vivo, they induced retinal pathology by subretinal injection of FITC-labeled Aβ. The effects of Humanin on mitochondrial clearance, retinal function, and RPE barrier integrity were then assessed. In vitro, ARPE-19 cells were used to elucidate the underlying molecular mechanisms, focusing on AMPK activation, ULK1 and Beclin1 phosphorylation, and Parkin interaction/translocation to mitochondria, all indicative of mitophagy induction.

In an in vivo model of Aβ-induced retinal pathology, Humanin (HN) administration was observed to enhance the clearance of Aβ-accumulated mitochondria within the retinal pigment epithelium (RPE). This mitochondrial clearance was associated with the preservation of overall retinal function and the integrity of the RPE barrier, both critical for healthy vision.

Mechanistically, in ARPE-19 cells, Humanin activated AMP-activated protein kinase (AMPK). This activation subsequently led to the phosphorylation of ULK1 and Beclin1, key proteins in the autophagy pathway. The phosphorylation of Beclin1 specifically promoted its interaction with Parkin, a ubiquitin ligase crucial for mitophagy, and facilitated their translocation to mitochondria. This coordinated cellular process ultimately resulted in the efficient removal of dysfunctional, Aβ-accumulated mitochondria from the RPE cells. The abstract did not provide specific quantitative data (e.g., percentages, p-values, fold-changes) for these observations.