Melanin precursors mediated adaption to temperature changes in fungus and animal via inhibition of lipid-mediated ferroptosis
image: A common polyketide-derived metabolite was exploited by the thermophilic fungus to function as an alternative ferroptosis defensive system in response to temperature change. Art by Xuemei NIU group. view more
Credit: ©Science China Press
Natural products are a rich source of lead compounds for new drugs. The discovery of biological activities of natural products plays a vital part in drug development and therapeutic strategies. The original functions and the underlying mechanisms of the metabolites in their hosts’ adaptation to environmental changes are led by Dr. Xuemei NIU (State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University) and Dr. Shenghong Li (State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences). Chemical investigation on thermophilic fungi all over the world were conducted by Xumei Niu at State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan. Dr. Yang noticed dark colony growth when a predominant thermophilic fungus cultivated at a relative low temperature 37°C instead of at its optimal temperature 50°C. Metabolic analysis and chemical investigation characterized the accumulation of a polyketide metabolite as the melanin precursor in the fungus in response to temperature change from 50°C to 37°C. A mutant deficient in the melanin precursor was constructed via a modified thermophilic CRISPR/Cas9 system. Microscopic analyses of the conidia and mycelia from the wide-type and the mutant strains were conducted. The researchers observed that the mutant at 37°C displayed abnormal cell walls (see left image below). Internally, tinted lipid droplets in conidia (see left image below) and the disrupted mitochondrial cristae and the outer mitochondrial membrane, diagnostic for ferroptosis, in mycelia (see right image below), were also visible. "I couldn't believe it, my heart almost stopped beating," Xuemei NIU says.
To determine whether temperature change could induce ferroptosis in the mutant. The researchers performed a series of biochemical and transcriptional analysis relative to lipid and ferroptosis. The team found that loss of the melanin precursor could induce cold stress-induced ferroptosis in the fungus. The chemical complementation test of the mutant with the precursor supports the anti-ferroptosis function of the melanin precursor in the fungus under cold stress.
Considering that 1) temperature changes are one of the key factors that influence all the living organisms; 2) melanins are the most abundant polymers in animal pigmentation; and 3) ferroptosis has been well characterized in mammal models, the researchers hypothesized that the role of melanin in controlling cold stress-induced ferroptosis might be a general phenomenon in living organisms including mammals. Therefore, the teams were inspired to investigate the mice and mice cells at different temperatures. As expected, mice with melanin displayed increased resistance to cold stress. The addition of the melanin precursors could inhibit cold stress-induced ferroptosis in mice cells. These new exciting results provided a mechanistic insight into “catching cold” due to innate boosting ferroptosis in organisms and offered an interpretation of the possible ultimate goal of the melanin pigmentation as “anti-cold” tactic. We hope that this study will encourage scientists working on small molecular metabolites to reveal all the unknown secrets that the natural products have" Xuemei Niu says. This would also help develop a new strategy and target for the prevention and treatment of pathogen infection.
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Melanin Precursors Mediated Adaption to Temperature Changes in Fungus and Animal via Inhibition of Lipid-Mediated Ferroptosis