Mitochondria–Lipid Crosstalk and Ferroptosis in Dry Age-Related Macular Degeneration: A Systematic Review

Abstract

Background Dry Age-Related Macular Degeneration (AMD) is a leading cause of vision loss in older adults, characterized by the progressive degeneration of retinal cells. Recent studies suggest that mitochondrial dysfunction, altered lipid metabolism, and ferroptosis (iron-dependent cell death) play pivotal roles in the development and progression of dry AMD. This systematic review explores the interactions between mitochondria, lipid metabolism, and ferroptosis in AMD pathogenesis, as well as potential therapeutic strategies targeting these pathways.

Objective To systematically review and synthesize the current evidence on the role of mitochondria–lipid crosstalk and ferroptosis in dry AMD, and to evaluate potential therapeutic approaches targeting these mechanisms.

Methods A systematic search was conducted across electronic databases including PubMed, Scopus, and Web of Science to identify studies published up to March 2025. Studies included in the review were those that investigated mitochondrial dysfunction, lipid metabolism, and ferroptosis in the context of dry AMD. Both experimental and clinical studies were considered. Data were extracted on mitochondrial impairment, lipid alterations, ferroptosis markers, and therapeutic interventions.

Results Five studies were included in the review. The findings consistently highlighted the role of mitochondrial dysfunction in increasing oxidative stress, which leads to lipid peroxidation and subsequent ferroptosis in retinal cells. These processes were found to contribute to retinal degeneration in AMD. The reviewed studies reported increased lipid peroxidation and elevated ferroptosis markers in AMD-affected retinal tissues, particularly in the retinal pigment epithelium (RPE) and photoreceptors. Moreover, therapeutic strategies targeting mitochondrial protection, lipid metabolism modulation, and ferroptosis inhibition, such as antioxidant therapies, iron chelation, and lipid-peroxidation inhibitors, showed promise in mitigating retinal cell damage.

Conclusions Mitochondrial dysfunction, lipid peroxidation, and ferroptosis are critical contributors to the pathogenesis of dry AMD. The interplay between these factors accelerates retinal cell death and disease progression. Targeting mitochondrial dysfunction, lipid metabolism, and ferroptosis may offer new therapeutic opportunities to slow or prevent the progression of dry AMD. However, further clinical studies are needed to evaluate the efficacy of these potential therapies in AMD treatment.