Alternative oxidase promotes high iron tolerance in Candida albicans

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 mu M. 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.

Automated summary

This study reveals the crucial role of alternative oxidase (AOX) in protecting mitochondria from high iron-induced reactive oxygen species (ROS) damage in the fungal pathogen C. albicans.