Labile iron overload reprograms microglia and neurons for lipid droplet synthesis in the aging brain

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.

University of California, San Diego · biorxiv

Paper

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

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Research summary

The paper claims that labile iron overload drives lipid droplet formation in aging microglia and neurons through a mitochondrial-iron axis and reactive oxygen species. This research addresses mechanisms underlying cellular dysfunction in the aging brain, which is pertinent to understanding and potentially mitigating age-related decline.

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