Thermomyces lanuginosus strain:0065 Raw sequence reads. Thermomyces lanuginosus strain:0065

In this work, we first compared the phenotypic, metabolic and transcriptional responses of common thermophilic fungus Thermomyces lanuginosus (TL) at two temperatures, its minimum growth temperature at 37 and its optimal growth temperature at 50. Chemical investigations led to isolation and characterization of a simple polyketide derived (PK) metabolite (1) that was involved in melanin biosynthesis induced by cold stress. A combination of CRISPR/Cas9 genetic manipulation and chemical screening led to successful construction of a mutant devoid of 1, which displayed sharply decreased survival rate and viability under cold stress. Electron microscopy analysis revealed dramatically increased lipid droplets in the mutant with lack of mitochondrial cristae and membranes, cytological markers diagnostic for ferroptosis. A series of ferroptosis assays combined with chemically complementary bioassays revealed that lack of 1 caused a cascade of detrimental changes, leading to lipid mediated ferroptosis in the fungus under cold stress. Considering that melanin is the most abundant polymer contributing to animal pigmentation, we also evaluated the role of melanin in mice under cold stress. It was found that melanin could also lower lipid level and improve mice resistance to cold stress. Further analysis revealed that melanin precursors could significantly attenuate lipid mediated ferroptosis in mouse cells under cold stress.