Alternative oxidase promotes high iron tolerance in Candida albicans.
Alternative oxidase promotes high iron tolerance in Candida albicans.
复制标题
DOI：
10.1128/spectrum.02157-23
复制
发表时间：
2023-12-12
影响因子：
3.7
通讯作者：
Puri S
中科院分区：
文献类型：
--
作者：
Sharma R;Gibb AA;Barnts K;Elrod JW;Puri S
尽管铁对细胞功能至关重要，但如果铁过量存在，它是有毒的。铁超载会造成不稳定的铁池(LIP)，损害线粒体，导致氧化呼吸中断。真菌病原菌白念珠菌具有一种非常规的末端氧化酶[交替氧化酶(AOX)]，它可以破坏电子传递链，消除各种应激源产生的多余电子，从而保护呼吸器官。在这里，我们确定了AOX在高铁条件下的一个新角色，即它充当保护线粒体免受高铁诱导的活性氧(ROS)影响的“安全阀”。白念珠菌对环境铁表现出明显的代谢灵活性，范围从1到500微米。高铁显著增加细胞内铁、LIP和细胞内ROS水平。铁诱导AOX1/2的表达，缺失AOX1/2的细胞在高铁条件下表现出高水平的线粒体ROS和明显的生长缺陷。因此，Aox1/2有助于减轻铁的负面影响。此外，铁诱导的AOX1/2的表达是间歇性的，因此尽管AOX是非质子动机，但仍可防止ATP丢失。高铁条件下线粒体耗氧率(OCR)显著高于对照组(62.8%)。与低铁条件下的Aox1/2相比，Aox1/2对这种高OCR的贡献更大。最后，当缺乏AOX1/2的真菌细胞用于小鼠感染时，在高铁条件下观察到的对野生型细胞的增强的白色念珠菌的毒力消失了。因此，AOX对于保护线粒体功能以在高铁宿主中生存至关重要。白念珠菌表现出新陈代谢的灵活性，以适应宿主对包括铁等必需金属在内的各种营养物质的可获得性。例如，血液是缺铁的，而口腔和肠腔则被认为是铁充足的。我们在这里表明，白色念珠菌可以耐受非常高水平的环境铁，尽管高铁诱导的活性氧物种(ROS)增加，它在一种独特的酶，称为替代酶(AOX)的帮助下减轻。高铁诱导AOX1/2，从而限制线粒体ROS的积累。AOX1/2的基因消除导致高铁小鼠口咽念珠菌病期间毒力降低。由于人类线粒体缺乏AOX蛋白，因此它是治疗真菌感染的独特靶点。
Although crucial for cellular functioning, iron is toxic when present in excess. Iron overload can create a labile iron pool (LIP) that harms the mitochondrion, resulting in disruption of oxidative respiration. Fungal pathogen C. albicans possesses an unconventional terminal oxidase [alternative oxidase (AOX)] that can disrupt the electron transport chain to remove excess electrons, generated from various stressors, to shield the respiratory apparatus. Here, we identify a novel role for AOX under high iron, whereby it works as “safety valve” to protect the mitochondrion from high iron-induced reactive oxygen species (ROS). C. albicans showed pronounced metabolic flexibility to environmental iron, ranging from 1 to 500 µM. High iron significantly increased intracellular iron, LIP, and levels of cellular ROS. Expression of both AOX1/2 was induced by iron, and cells lacking Aox1/2 showed high levels of mitochondrial ROS as well as significant growth defect under high iron. Thus, Aox1/2 helps mitigate the negative effects of iron. Furthermore, iron-induced expression of AOX1/2 was intermittent, thus preventing ATP loss despite AOX being non-proton motive. Mitochondrial oxygen consumption rate (OCR) was significantly higher (62.8%) under high iron conditions. Contribution of Aox1/2 was greater toward this high OCR, compared to their contribution in low iron conditions. Lastly, enhanced virulence of C. albicans that is observed for wild-type cells under high iron was lost when fungal cells lacking AOX1/2 were used for murine infection. Thus, AOX is crucial for preserving mitochondrial function for survival in a high iron host. The yeast C. albicans exhibits metabolic flexibility for adaptability to host niches with varying availability of nutrients including essential metals like iron. For example, blood is iron deplete, while the oral cavity and the intestinal lumen are considered iron replete. We show here that C. albicans can tolerate very high levels of environmental iron, despite an increase in high iron-induced reactive oxygen species (ROS) that it mitigates with the help of a unique oxidase, known as alternative oxidase (AOX). High iron induces AOX1/2 that limits mitochondrial accumulation of ROS. Genetic elimination of AOX1/2 resulted in diminished virulence during oropharyngeal candidiasis in high iron mice. Since human mitochondria lack AOX protein, it represents a unique target for treatment of fungal infections.
登录
查看更多内容
影响因子：
6.7
作者：
Grahl N;Demers EG;Lindsay AK;Harty CE;Willger SD;Piispanen AE;Hogan DA
通讯作者：
Hogan DA
DOI：
10.3390/antiox10020313
发表时间：
2021-02-19
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Herb M;Schramm M
通讯作者：
Schramm M
影响因子：
3.9
作者：
通讯作者：
--
影响因子：
4.1
作者：
Huh, WK;Kang, SO
通讯作者：
Kang, SO
影响因子：
2.6
作者：
Hwang, CS;Baek, YU;Kang, SO
通讯作者：
Kang, SO