A PPAR-gamma counterpart protects worm neurons by coordinating lipids and mitochondria

In Caenorhabditis elegans, researchers identified the nuclear receptor SEX-1 as a functional counterpart to mammalian PPARγ. Using comparative genomics, multi-omics profiling, and experimental testing, the team investigated how this receptor coordinates metabolism to protect neurons. They found that SEX-1 orchestrates membrane sphingolipid metabolism, lipid droplet dynamics, and mitochondrial quality control via lipogenic and autophagic programs. Loss of sex-1 caused abnormal lipid droplet buildup, mitochondrial dysfunction, and altered sphingolipid metabolism. These disruptions harmed the structural integrity and thermosensory function of amphid sensory neurons during early adulthood. The ability of SEX-1 to restrict lipid droplet accumulation also declined with age. Genetically altering sphingolipid pathways rescued the neuronal defects, linking lipid homeostasis directly to neuron survival.