AMPK Repositions Early Endosomes via Gapex-5 to Promote Delivery of Iron to Mitochondria

The regulation of the spatial organization of organelles within cells is critical for coordinating signaling, membrane traffic, and metabolite exchange. Metabolic cues regulate the position and function of lysosomes, yet whether and how metabolic signals may similarly regulate other organelles such as early endosomes (EEs) remains unclear. We find that AMP-activated protein kinase (AMPK), a key regulator of metabolic homeostasis activated in response to nutrient scarcity, triggers movement of EEs to the perinuclear region of cells, leading to enhanced proximity of endosomes to mitochondria and increased delivery of iron to mitochondria. The movement of EEs and increased mitochondrial iron content elicited by AMPK activation requires Gapex-5, a GEF for the early endosome Rab5 previously shown to be an AMPK substrate. These findings reveal a mechanism by which AMPK reprograms endosome positioning to facilitate inter-organelle communication and iron delivery to mitochondria to support metabolic adaptation under conditions of nutrient scarcity.