Mol Neurobiol. 2025 Mar 18. doi: 10.1007/s12035-025-04832-6. Online ahead of print.
ABSTRACT
Age-related macular degeneration (AMD) is the leading cause of vision impairment among older aged people. Recent studies have indicated that focusing on the underlying mechanism of ferroptosis (a form of iron-dependent cell death) could be crucial in understanding the progression of AMD, as it is strongly linked with inflammation. However, the specific dependence of ferroptosis on the mitochondria in the retinal pigment epithelium (RPE) and its surrounding immune cells remains unclear. In this study, we showed that mitochondria were required for the proliferation and maintenance of the RPE by regulating the expression of genes implicated in both pro- and antiferroptosis activities. Under chemically induced hypoxic conditions, Wt-ARPE-19 cells (basal mitochondrial level) increased the expression of genes linked with antiferroptotic activity. In contrast, rho0-ARPE-19 cells (mitochondria depleted) did not stimulate either pro- or antiferroptosis gene expression. However, diff-ARPE-19 cells (abundant in mitochondria) presented an improved proferroptotic activity. Furthermore, we demonstrated that mitochondria regulated monocyte differentiation into macrophages, resulting in differential expression of pro- and antiferroptotic factors. Through a direct coculture approach, the absence of mitochondria in ARPE-19 cells was shown to influences monocyte differentiation toward an inflammatory phenotype. This differentiation might increase ferroptosis activity. Transmitochondrial cybrids derived from patients with dry AMD and age-matched controls without dry AMD presented elevated mtDNA copy numbers, leading to increased ferritinophagy and increased levels of polyunsaturated fatty acids. These data highlighted that ferroptosis was partly regulated by mitochondria and that understanding the mechanisms governing the relationship between mitochondria and ferroptosis may open new potential avenues for managing dry AMD.
PMID:40100494 | DOI:10.1007/s12035-025-04832-6