Okamoto Michiyo, Nakano Keiko, Takahashi-Nakaguchi Azusa, Sasamoto Kaname, Yamaguchi Masashi, Teixeira Miguel Cacho, Chibana Hiroji
Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal.
J Fungi (Basel). 2023 Feb 10;9(2):240. doi: 10.3390/jof9020240.
Mitochondrial dysfunction or morphological abnormalities in human pathogenic fungi are known to contribute to azole resistance; however, the underlying molecular mechanisms are unknown. In this study, we investigated the link between mitochondrial morphology and azole resistance in , which is the second most common cause of human candidiasis worldwide. The ER-mitochondrial encounter structure (ERMES) complex is thought to play an important role in the mitochondrial dynamics necessary for mitochondria to maintain their function. Of the five components of the ERMES complex, deletion of increased azole resistance. Gem1 is a GTPase that regulates the ERMES complex activity. Point mutations in GTPase domains were sufficient to confer azole resistance. The cells lacking displayed abnormalities in mitochondrial morphology, increased mtROS levels, and increased expression of azole drug efflux pumps encoded by and . Interestingly, treatment with N-acetylcysteine (NAC), an antioxidant, reduced ROS production and the expression of in Δ cells. Altogether, the absence of Gem1 activity caused an increase in mitochondrial ROS concentration, leading to Pdr1-dependent upregulation of the drug efflux pump Cdr1, resulting in azole resistance.
已知人类致病真菌中的线粒体功能障碍或形态异常会导致唑类耐药；然而，其潜在的分子机制尚不清楚。在本研究中，我们调查了在全球范围内作为人类念珠菌病第二大常见病因的白色念珠菌中线粒体形态与唑类耐药之间的联系。内质网-线粒体接触结构（ERMES）复合体被认为在维持线粒体功能所必需的线粒体动力学中发挥重要作用。在ERMES复合体的五个组分中，删除Gem1会增加唑类耐药性。Gem1是一种调节ERMES复合体活性的GTP酶。Gem1 GTP酶结构域中的点突变足以赋予唑类耐药性。缺乏Gem1的细胞表现出线粒体形态异常、线粒体活性氧（mtROS）水平升高以及由CDR1和CDR2编码的唑类药物外排泵的表达增加。有趣的是，用抗氧化剂N-乙酰半胱氨酸（NAC）处理可降低ΔGem1细胞中的ROS产生以及CDR1的表达。总之，Gem1活性的缺失导致线粒体ROS浓度增加，从而导致药物外排泵Cdr1的Pdr1依赖性上调，进而产生唑类耐药性。
