Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process

• Published in: Nature communications 2022-09, Vol.13 (1), p.5407-5407, Article 5407
• Main Authors: Gao, Xindi, Fu, Yi, Sun, Shengyi, Gu, Tingyi, Li, Yanjian, Sun, Tianshu, Li, Hailong, Du, Wei, Suo, Chenhao, Li, Chao, Gao, Yiru, Meng, Yang, Ni, Yue, Yang, Sheng, Lan, Tian, Sai, Sixiang, Li, Jiayi, Yu, Kun, Wang, Ping, Ding, Chen
• Format: Article
• Language: English
• Subjects: 38; 38/15; 42; 631/326/193/2538; 631/326/421; 631/337/572/2102; 82/103; 82/58; Accumulation; Apoptosis; Binding; Cell death; Cryptococcus neoformans; Damage; Deoxyribonucleic acid; DNA; DNA damage; Electron transfer; Fungal infections; Fungi; Gene expression; Genes; Genomes; Genomic instability; Heat shock; Heat shock factors; Homeostasis; Humanities and Social Sciences; Medical and Health Sciences; Medical Biotechnology; Medicin och hälsovetenskap; Medicinsk bioteknologi; Mitochondria; multidisciplinary; Oxidation; Oxygen; Protected species; Protein folding; Proteins; Quality control; Reactive oxygen species; Respiration; Science; Science (multidisciplinary); Stresses; Tricarboxylic acid cycle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33168-1

Mitochondrial quality control prevents accumulation of intramitochondrial-derived reactive oxygen species (mtROS), thereby protecting cells against DNA damage, genome instability, and programmed cell death. However, underlying mechanisms are incompletely understood, particularly in fungal species. Here, we show that Cryptococcus neoformans heat shock factor 3 ( Cn Hsf3) exhibits an atypical function in regulating mtROS independent of the unfolded protein response. Cn Hsf3 acts in nuclei and mitochondria, and nuclear- and mitochondrial-targeting signals are required for its organelle-specific functions. It represses the expression of genes involved in the tricarboxylic acid cycle while promoting expression of genes involved in electron transfer chain. In addition, Cn Hsf3 responds to multiple intramitochondrial stresses; this response is mediated by oxidation of the cysteine residue on its DNA binding domain, which enhances DNA binding. Our results reveal a function of HSF proteins in regulating mtROS homeostasis that is independent of the unfolded protein response. Mitochondrial quality control prevents accumulation of intramitochondrial reactive oxygen species (mtROS), thus protecting cells against DNA damage. Here, Gao et al. show that an atypical heat shock factor responds to intramitochondrial stresses and regulates mtROS homeostasis in the pathogenic fungus Cryptococcus neoformans .