Melanin regulates mitochondrial dynamics, metabolism and inflammatory signaling to protect the retina

Abstract Albino individuals are clinically recognized to exhibit heightened susceptibility to light-induced retinal injury, yet the cellular and metabolic mechanisms underlying this vulnerability remain poorly defined. Here, we investigated whether retinal pigment epithelium (RPE) pigmentation governs mitochondrial structure, metabolism, and inflammatory responses that ultimately determine retinal resilience to blue light stress. Using pigmented (C57BL/6J) and albino (Balb/c) mice, we demonstrate that albino animals exhibit markedly increased retinal phototoxicity following blue light exposure, manifested by fundus lesions, outer nuclear layer (ONL) disruption, and structural degeneration evident by OCT. Primary RPE cultures derived from albino mice exhibited profound difference in mitochondrial morphology, characterized by increased mitochondrial number, reduced size, and enhanced fragmentation, accompanied by elevated mitochondrial DNA copy number. These structural changes correlated with transcriptional skewing toward mitochondrial fission (increased Drp1) and suppression of mitochondrial fusion (Mfn1, Mfn2, OPA1). Functionally, albino and depigmented RPE displayed impaired oxidative phosphorylation, reduced ATP production, and diminished reliance on mitochondrial pyruvate carrier (MPC)–dependent metabolism. In parallel, albino RPE demonstrated cell-cycle accumulation at G2/M and heightened basal and blue light-induced secretion of pro-inflammatory cytokines, particularly IFN-β1, IL-6, and TNF-α. Importantly, exogenous melanin supplementation partially restored mitochondrial fusion gene expression, pyruvate-dependent respiration, and inflammatory restraint. Together, these findings identify melanin as a critical regulator of RPE mitochondrial architecture, metabolic substrate utilization, and inflammatory signaling, providing a mechanistic framework to explain enhanced photo-vulnerability in the albino retina. These insights establish pigmentation-dependent mitochondrial metabolism as a determinant of retinal resilience and suggest mitochondrial bioenergetics as a therapeutic target. Competing Interest Statement Competing interests: Z.H. has filed an invention disclosure related to aspects of this work through the UNC Office of Technology Commercialization (OTC) (Disclosure No. 24-0018).