Loss of Ssq1 leads to mitochondrial dysfunction, activation of autophagy and cell cycle arrest due to iron overload triggered by mitochondrial iron-sulfur cluster assembly defects in Candida albicans.
Iron-sulfur clusters perform essential functions in enzymatic catalysis and homeostatic regulation. Here we for the first time identified Ssq1 as an essential component for iron-sulfur cluster assembly in Candida albicans. Ssq1 played an important role in cell growth. Shutting off SSQ1 led to accumulation of intracellular iron, especially in mitochondria, and disorder of intracellular iron regulation. In tetO-SSQ1, iron overloading triggered the oxidative damage of mitochondrial function. Surprisingly, disruption of SSQ1 activated autophagic pathway. The mitochondrial dysfunction was further aggravated when CCZ1 (which is essential for autophagy) and SSQ1 was simultaneously deleted, suggesting that autophagy played a critical role in maintenance of mitochondrial function in tetO-SSQ1. In addition, double deletion of SSQ1 and CCZ1 further elevated cellular iron levels in comparison with tetO-SSQ1, indicating that autophagy participated in maintenance of iron homeostasis. Furthermore, we found that loss of SSQ1 led to increasing protein expression of Rnr1 and redistribution of Rnr2 from the nucleus to cytoplasm, and further resulted in cell cycle arrest. The results implied that cell cycle arrest was caused by activating the checkpoint pathway because of impairing the iron-sulfur cluster assembly in tetO-SSQ1. Shutting off SSQ1 led to a significant defect in filamentous development. Interestingly, the tetO-SSQ1ccz1Δ/Δ growth was inhibited on hyphae-inducing solid media. Both tetO-SSQ1 and tetO-SSQ1ccz1Δ/Δ exhibited extremely attenuated virulence, indicating that Ssq1 might provide a promising target for antifungal drugs development. In summary, our findings provide new insights into the understanding of iron-sulfur cluster assembly-related gene in C. albicans.
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China; The State Key Laboratory for Biology of Plant Disease and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, PR China.
Yijie
Y
Dong
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Dan
D
Zhang
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Qilin
Q
Yu
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Qiang
Q
Zhao
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Chenpeng
C
Xiao
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Kai
K
Zhang
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Chang
C
Jia
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Sijia
S
Chen
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China.
Bing
B
Zhang
Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
Biao
B
Zhang
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, PR China. Electronic address: nklimingchun@163.com.
Mingchun
M
Li
D001343:Autophagy / Q000235:genetics*; D002176:Candida albicans / Q000166:cytology* / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000235:genetics* / Q000378:metabolism; D000073658:Loss of Function Mutation; D008928:Mitochondria / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics*; D008954:Models, Biological; D060888:Real-Time Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014774:Virulence / Q000235:genetics
D018840:HSP70 Heat-Shock Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; C115913:SSQ1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D007501:Iron
Candida albicans; Cell cycle; Iron homeostasis; Iron–sulfur cluster assembly; Mitochondrial dysfunction; autophagy