[Optical imaging probes for hypoxic biology]

Oxygen is essential for aerobic energy metabolism and also regulates the expression of genes involved in metabolic pathways through HIF-1. Energy metabolism is closely linked to cellular functions and disease states; therefore, quantitative knowledge of the spatio-temporal dynamics of oxygen levels and metabolic status is required to gain a deeper understanding of the relationships between oxygen, biological processes, and pathology. This review provides an overview of imaging probes for molecular oxygen and ATP, a representative metabolite of energy metabolism. For oxygen imaging, metal-complex-based probes that exploit the oxygen-dependent shortening of phosphorescence lifetime are most widely used. This approach offers high quantitative reliability with minimal dependence on excitation intensity or probe concentration. Recent advances in probes compatible with two-photon excitation have further enabled analysis of oxygen distribution in deep tissues in vivo. In parallel, genetically encoded oxygen probes based on fluorescent proteins have been developed; although their applications remain limited, these probes offer advantages in cell-type-specific expression and precise subcellular targeting. For ATP imaging, FRET-based probes such as ATeam/GO-ATeam, as well as single-fluorescent protein sensors including QUEEN, iATPSnFR, and MaLion, have been developed, allowing intracellular ATP dynamics to be analyzed with high spatiotemporal resolution. Moreover, the Avid mouse, which enables whole-body visualization of ATP dynamics, allows direct assessment of intratissue heterogeneity in ATP maintenance capacity and ATP-protective effects of pharmacological interventions. Collectively, these imaging technologies are expected to serve as important methodological foundations for understanding pharmacological actions by linking oxygen supply to energetic failure.