Kumari Deepika, Kumar Mohit, Gaur Naseem A, Duhan Lucky, Sachivkina Nadezhda, Manoharlal Raman, Pasrija Ritu
Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana 124001, India.
International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India.
J Cell Sci. 2025 May 1;138(9). doi: 10.1242/jcs.263558. Epub 2025 Apr 3.
Cryptococcus neoformans is a common fungal pathogen, causing fatal meningoencephalitis in immunocompromised individuals. The limited availability of antifungals and increasing resistance in pathogens including C. neoformans emphasize the need to find new drugs. Mitochondria have long been associated with drug resistance in fungi. They are connected to the endoplasmic reticulum (ER) via a multiprotein complex, the ER-mitochondria encounter structure (ERMES), which is unique in the fungal kingdom. In this study on C. neoformans, the four subunits of the ERMES complex, namely, Mmm1, Mdm12, Mdm10 and Mdm34, were deleted to generate the strains Δmmm1, Δmdm12, Δmdm10 and Δmdm34, respectively. These mutants had impaired mitochondria and were sensitive to antifungals, including echinocandins, due to lower chitin content. Virulence factors, including capsule formation and melanin production, were debilitated in the mutants. The partner organelle ER was also affected by compromised ERMES contact, as the activity of several ER-synthesized enzymes involved in virulence was impacted. The in vivo studies in Caenorhabditis elegans model of cryptococcosis confirmed the reduced virulence of the mutants. These results indicate that the impairment of the ERMES complex is crucial for the virulence and pathogenesis of C. neoformans.
新型隐球菌是一种常见的真菌病原体，可在免疫功能低下的个体中引发致命的脑膜脑炎。抗真菌药物的供应有限以及包括新型隐球菌在内的病原体耐药性不断增加，凸显了寻找新药的必要性。线粒体长期以来一直与真菌的耐药性有关。它们通过一种多蛋白复合物——内质网-线粒体接触结构（ERMES）与内质网（ER）相连，这种结构在真菌界是独一无二的。在这项针对新型隐球菌的研究中，删除了ERMES复合物的四个亚基，即Mmm1、Mdm12、Mdm10和Mdm34，分别产生了菌株Δmmm1、Δmdm12、Δmdm10和Δmdm34。这些突变体的线粒体受损，并且由于几丁质含量较低而对抗真菌药物敏感，包括棘白菌素。毒力因子，包括荚膜形成和黑色素产生，在突变体中减弱。伴侣细胞器内质网也受到ERMES接触受损的影响，因为几种参与毒力的内质网合成酶的活性受到影响。在秀丽隐杆线虫隐球菌病模型中的体内研究证实了突变体的毒力降低。这些结果表明，ERMES复合物的损伤对于新型隐球菌的毒力和发病机制至关重要。
