Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.

中文翻译：

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DGAT1 活性与线粒体自噬同步，以保护细胞免受铁耗尽导致的代谢重新布线。

Mitophagy 通过溶酶体消除去除有缺陷的线粒体。线粒体自噬的增加与代谢重编程同时发生，但线粒体自噬是这种状态变化的原因还是结果仍然未知。与线粒体自噬相结合以维持细胞和组织完整性的信号通路也仍然不明确。我们对用去铁酮处理的哺乳动物细胞进行了时间代谢组学，去铁酮是一种治疗性铁螯合剂，可刺激 PINK1/PARKIN 非依赖性线粒体自噬。铁耗竭深刻地重新连接了代谢组，其特点是在治疗几分钟内重塑了脂质代谢。DGAT1 依赖性脂滴生物合成发生在线粒体清除前几个小时，脂滴在铁螯合时与线粒体接壤。我们证明 DGAT1 抑制在体外限制线粒体自噬，溶酶体稳态和细胞活力受损。重要的是，体内 DGAT1 的基因缺失显着损害了果蝇的神经元线粒体自噬和运动功能。我们的数据将铁耗竭定义为一种强有力的信号，它可以迅速重塑新陈代谢，并在脂质稳态和线粒体自噬之间建立意想不到的协同作用，从而保护细胞和组织的完整性。