1 School of Pharmacy, Naval Medical University, Shanghai 200433, China.
2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
3 Beijing South Medical District of Chinese PLA General Hospital, Beijing 100072, China.
4 Department of Biology, Concordia University, Montreal, H4B 1R6 Quebec, Canada.
5 Basic Medicine Innovation Center for Fungal Infectious Diseases, (Naval Medical University), Ministry of Education, Shanghai 200433, China.
6 Key Laboratory of Biosafety Defense (Naval Medical University), Ministry of Education, Shanghai 200433, China.
7 Shanghai Key Laboratory of Medical Biodefense, Shanghai 200433, China.

In the respiratory chain of the majority of aerobic organisms, the enzyme alternative oxidase (AOX) functions as the terminal oxidase and has important roles in maintaining metabolic and signaling homeostasis in mitochondria. AOX endows the respiratory system with flexibility in the coupling among the carbon metabolism pathway, electron transport chain (ETC) activity, and ATP turnover. AOX allows electrons to bypass the main cytochrome pathway to restrict the generation of reactive oxygen species (ROS). The inhibition of AOX leads to oxidative damage and contributes to the loss of adaptability and viability in some pathogenic organisms. Although AOXs have recently been identified in several organisms, crystal structures and major functions still need to be explored. Recent work on the trypanosome alternative oxidase has provided a crystal structure of an AOX protein, which contributes to the structure-activity relationship of the inhibitors of AOX. Here, we review the current knowledge on the development, structure, and properties of AOXs, as well as their roles and mechanisms in plants, animals, algae, protists, fungi, and bacteria, with a special emphasis on the development of AOX inhibitors, which will improve the understanding of respiratory regulation in many organisms and provide references for subsequent studies of AOX-targeted inhibitors.