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bioRxiv · 10.1101/2025.06.10.658522

Complex I Governs Iron Levels in Bat Mitochondria to Couple Respiration with Lipid Metabolism

Zeng, W.·Peng, P.·Chen, C.·Wang, D.·Cao, L.·Wang, Z.·Xia, Y.·Qiu, J.
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Abstract

The evolution of mitochondrial respiration has been implicated in the remarkable adaptations of bats, including powered flight, longevity and viral tolerance. However, the mechanisms coordinating mitochondrial respiration with lipid metabolism--a critical energy source for flight--remain poorly understood. Here, we discovered that complex I inhibition triggered iron overload into bat mitochondria, inducing a burst of reactive oxygen species (ROS). This iron translocation relied on the VDAC-MCU axis and mitochondrial membrane potential. Intriguingly, disrupting VDAC oligomerization enhanced iron uptake in a complex I-dependent manner. Mitochondrial iron translocation perturbed fatty acid oxidation and upregulated linoleic acid species, which promoted the reversible accumulation of lipid droplets, suggesting metabolic plasticity crucial for bat energetics. Our findings establish complex I as a pivotal regulatory hub that directly couples respiratory efficiency to lipid metabolism by governing mitochondrial iron levels. This mechanism may represent a key evolutionary adaptation supporting the unique metabolic demands of bat physiology. HIGHLIGHTSComplex I inhibition induces unique mitochondrial ROS burst in bat cells. Mitochondrial iron overload is the primary trigger of complex I-linked ROS burst. VDAC-MCU axis couples membrane potential to drive mitochondrial iron influx. Mitochondrial iron translocation remodels lipid metabolism in bat cells.

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Zeng, W., Peng, P., Chen, C., Wang, D., Cao, L., Wang, Z., Xia, Y., Qiu, J.. 2025-06-11. Complex I Governs Iron Levels in Bat Mitochondria to Couple Respiration with Lipid Metabolism. https://doi.org/10.1101/2025.06.10.658522

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