Kumari Deepika, Bari Vinay Kumar, Pasrija Ritu
Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, 124001, India.
Department of Biochemistry, Central University of Punjab, Bathinda, Punjab, 151401, India.
Arch Microbiol. 2025 Aug 27;207(10):237. doi: 10.1007/s00203-025-04448-3.
Fungal infections pose a significant global health challenge, exacerbated by limited antifungal therapies and the rise of drug-resistant strains. The cell wall is a critical determinant of fungal pathogenicity, as it maintains structural integrity and mediates host-pathogen interactions. Notably, the cell wall compositions of Cryptococcus neoformans and Candida albicans differ substantially. In C. albicans, the inner layer is rich in chitin, β-1,3-glucans and β-1,6-glucans, while the outer layer comprises N-linked and O-linked mannoproteins. Conversely, C. neoformans includes additional components such as α-1,3-glucan and chitosan, and is characterized by an outermost capsule layer containing glucuronoxylomannan (GXM) and galactoxylomannan (GalXM), along with minor mannoproteins. In this study, we explored the role of a unique fungal multi-subunit complex known as the Endoplasmic Reticulum-Mitochondria Encounter Structure (ERMES) in regulating cell wall architecture. The ERMES complex is composed of four key subunits: Mmm1, Mdm10, Mdm12 and Mdm34. It plays critical roles across various fungal species, including maintaining mitochondrial morphology and function, facilitating phospholipid transport, supporting mitophagy and contributing to virulence. Notably, disruption of ERMES components has been linked to enhanced susceptibility of both planktonic and biofilm-forming fungal cells to echinocandin-class antifungal drugs. Our investigation revealed that deletion or impairment of ERMES subunits significantly alters the cell wall composition in C. neoformans and C. albicans, suggesting a previously underappreciated connection between mitochondrial contact sites and fungal cell wall integrity. Using staining techniques, we assessed changes in key cell wall components, including reduced β-1,3-glucans, chitin, chitosan and mannoproteins in deletion mutants (Δmmm1, Δmdm10, Δmdm12 and Δmdm34) of both species. Transmission electron microscopy (TEM) analysis confirmed alterations in cell wall thickness, with the most pronounced effects observed in Δmmm1 and Δmdm10 mutants. The ERMES mutants were also impaired in hyphal development. These findings underscore the essential role of ER-mitochondrial communication in regulating cell wall biosynthesis and structural remodeling.
真菌感染构成了重大的全球健康挑战，抗真菌治疗手段有限以及耐药菌株的增加使这一挑战更加严峻。细胞壁是真菌致病性的关键决定因素，因为它维持结构完整性并介导宿主与病原体的相互作用。值得注意的是，新型隐球菌和白色念珠菌的细胞壁组成有很大差异。在白色念珠菌中，内层富含几丁质、β-1,3-葡聚糖和β-1,6-葡聚糖，而外层由N-连接和O-连接的甘露糖蛋白组成。相反，新型隐球菌包含其他成分，如α-1,3-葡聚糖和壳聚糖，其特征是最外层的荚膜层含有葡糖醛酸木糖甘露聚糖（GXM）和半乳糖木糖甘露聚糖（GalXM），以及少量甘露糖蛋白。在本研究中，我们探讨了一种独特的真菌多亚基复合物，即内质网-线粒体接触结构（ERMES）在调节细胞壁结构中的作用。ERMES复合物由四个关键亚基组成：Mmm1、Mdm10、Mdm12和Mdm34。它在各种真菌物种中都起着关键作用，包括维持线粒体形态和功能、促进磷脂运输、支持线粒体自噬以及影响毒力。值得注意的是，ERMES成分的破坏与浮游和形成生物膜的真菌细胞对棘白菌素类抗真菌药物的易感性增加有关。我们的研究表明，ERMES亚基的缺失或功能受损会显著改变新型隐球菌和白色念珠菌的细胞壁组成，这表明线粒体接触位点与真菌细胞壁完整性之间存在以前未被充分认识的联系。我们使用染色技术评估了关键细胞壁成分的变化，包括两种菌的缺失突变体（Δmmm1、Δmdm10、Δmdm12和Δmdm34）中β-1,3-葡聚糖、几丁质、壳聚糖和甘露糖蛋白的减少。透射电子显微镜（TEM）分析证实了细胞壁厚度的改变，在Δmmm1和Δmdm10突变体中观察到的影响最为明显。ERMES突变体在菌丝发育方面也存在缺陷。这些发现强调了内质网-线粒体通讯在调节细胞壁生物合成和结构重塑中的重要作用。
