Authors
Cunha e Rocha, K., Xiang, Q., Qian, C., Wang, L., Yuan, W., Beldona, V., Duan, Y., Veras, L., Abolmaali, D., An, G., Park, J., Lim, W., Chen, X., Ying, W.
Abstract
Lipid-droplet (LD) accumulation emerges in microglia and neurons with age. Because neither cell type is specialized for lipid storage, LDs are linked to dysfunction. The upstream drivers of LD formation and their effects on neighboring cells remain unclear. Here, we identify a mitochondrial-iron axis that promotes LD formation in aging microglia via reactive oxygen species (ROS), which secondarily reshapes neuronal iron handling. LD-enriched microglia show reduced mitochondrial mass and increased labile iron, ROS, and lipid peroxidation. Chelating labile iron or scavenging ROS suppresses LD formation. Conditioned media from iron-stressed microglia alter neuronal iron homeostasis, indicating transcellular coupling. In primary neurons, iron overload increases LDs and activates coordinated iron, ROS, and lipogenesis programs, whereas antioxidant treatment attenuates iron-driven LD accumulation. Together, these findings position iron overload as an upstream regulator of ROS-dependent LD biogenesis in microglia and neurons and reveal a microglia
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Nov 2025.
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