Iron-depletion promotes mitophagy to maintain mitochondrial integrity in pathogenic yeast <i>Candida glabrata</i>

<i>Candida glabrata</i>, a haploid budding yeast, is the cause of severe systemic infections in immune-compromised hosts. The amount of free iron supplied to <i>C. glabrata</i> cells during systemic infections is severely limited by iron-chelating proteins such as transferrin. Thus, the iron-deficiency response in <i>C. glabrata</i> cells is thought to play important roles in their survival inside the host's body. In this study, we found that mitophagy was induced under iron-depleted conditions, and that the disruption of a gene homologous to <i>ATG32</i>, which is responsible for mitophagy in <i>Saccharomyces cerevisiae</i>, blocked mitophagy in <i>C. glabrata</i>. The mitophagic activity in <i>C. glabrata</i> cells was not detected on short-period exposure to nitrogen-starved conditions, which is a mitophagy-inducing condition used in <i>S. cerevisiae</i>. The mitophagy-deficient <i>atg32</i>Δ mutant of <i>C. glabrata</i> also exhibited decreased longevity under iron-deficient conditions. The mitochondrial membrane potential in <i>Cgatg32</i>Δ cells was significantly lower than that in wild-type cells under iron-depleted conditions. In a mouse model of disseminated infection, the <i>Cgatg32</i>Δ strain resulted in significantly decreased kidney and spleen fungal burdens compared with the wild-type strain. These results indicate that mitophagy in <i>C. glabrata</i> occurs in an iron-poor host tissue environment, and it may contribute to the longevity of cells, mitochondrial quality control, and pathogenesis.

光滑假丝酵母（Candida glabrata）是一种单倍体出芽酵母，可引发免疫受损宿主的严重系统性感染。在系统性感染过程中，转铁蛋白（transferrin）等铁螯合蛋白会大幅限制供给该菌细胞的游离铁含量。因此，学界普遍认为该菌的缺铁应答在其宿主内存活过程中发挥关键作用。本研究发现，缺铁条件可诱导线粒体自噬（mitophagy）的发生；酿酒酵母（Saccharomyces cerevisiae）中负责线粒体自噬的基因ATG32的同源基因被敲除后，会阻断光滑假丝酵母的线粒体自噬过程。相较于酿酒酵母中用于诱导线粒体自噬的氮饥饿条件，短期暴露于该环境下的光滑假丝酵母细胞未检测到线粒体自噬活性。线粒体自噬缺陷的光滑假丝酵母atg32Δ突变株，在缺铁条件下的存活时长显著降低。缺铁条件下，Cgatg32Δ细胞的线粒体膜电位显著低于野生型细胞。在播散性感染小鼠模型中，Cgatg32Δ菌株的肾脏与脾脏真菌负荷均显著低于野生型菌株。上述结果表明，光滑假丝酵母的线粒体自噬可在宿主组织的缺铁微环境中发生，其可能有助于细胞存活、线粒体质量控制以及致病过程。

搜集汇总

背景与挑战

背景概述

该数据集提供了一项关于病原酵母Candida glabrata的研究补充材料，重点探讨铁缺乏如何诱导线粒体自噬以维持线粒体完整性。研究发现，ATG32基因同源物对线粒体自噬至关重要，其缺失会导致细胞在铁缺乏环境下寿命缩短、线粒体功能受损，并降低在小鼠感染模型中的致病性。这些结果揭示了线粒体自噬在宿主铁限制环境中的关键作用，有助于理解Candida glabrata的生存机制和致病过程。