Role of Mitochondrial Optical Redox Imaging in Modern Cancer Research (2024 Peter Vaupel Honorary Lecture).

The mitochondrial optical redox imaging (ORI), pioneered by the late Britton Chance and his coworkers starting from the 1950s, is mainly based on the intrinsic fluorescence of reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) containing flavin adenine dinucleotide (FAD). These two important metabolic coenzymes regulate many intracellular biochemical reactions including glycolysis, the Krebs cycle, and oxidative phosphorylation, and participate in the intricate interplay between metabolism and signaling. The optical redox ratio (ORR) of these two fluorescence signals is an indicator of mitochondrial metabolic and redox status. Chance and his coworkers not only studied redox status in cells and tissues based on the intrinsic fluorescence but also developed the Chance redox scanner in the 1970s-80s, which images the 3D distribution of NADH, Fp, and ORR ex vivo in snap-frozen tissues. The repertoire of ORI has been further strengthened and enriched with the modern technical advancements including state-of-the-art fluorescence, confocal, two-photon, and lifetime imaging microscopy. ORI has been extensively applied to (pre)cancer cells and tissues including clinical biopsies and patient tumor-derived organoids, to develop metabolic biomarkers for (pre)cancer diagnosis, prognosis, and treatment response. In this chapter, I illustrate the basic principles, main concepts and progresses, and future directions of ORI in cancer research.