Seasonal temperature fluctuations present a major survival challenge for insects, requiring physiological adaptation that confers resilience to cold stress. However, the hormone mechanisms governing mitochondrial adaptation to overcome cold stress remain poorly understood. Here, we identify that the endogenous ascaroside C9 (asc-C9) acts as a chemical signal that markedly improves survival following acute cold exposure by coupling lipolysis to mitochondrial adaptation. We show that diapause larvae maintain compact mitochondrial cristae and display 2.7-fold higher post-chill survival compare to non-diapause larvae, whose mitochondria undergo swelling and fragmentation. Cold stress triggers diapause-specific accumulation of asc-C9 (ascr#10) in the subcutaneous fat body. Exogenous asc-C9 recruits the adipokinetic hormone receptor (AKHR) to activate the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-uncoupling protein 4 (UCP4) axis, thereby stimulating mitochondrial biogenesis, enhance uncoupled respiration, lowering the adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio, and synchronously accelerate lipid mobilization and increasing cold resilience. This asc-C9-AKHR-mitochondria module is functionally conserved in Drosophila melanogaster and Caenorhabditis elegans, indicating that ascaroside-mediated metabolic reprogramming is an ancient stress-adaptation strategy. Our findings reveal a sentinel hormone-driven lipid-to-mitochondria circuit that enables insects to survive extreme cold through targeted mitochondrial flexibility.
Keywords: adipokinetic hormone receptor; ascarosides hormone; diapause; mitochondrial biogenesis; mitochondrial uncoupling; survival.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.