Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues

Cell-state diversity drives tissue adaptability, repair, and disease resilience, but capturing this complexity is a challenge. Current approaches rely on transcriptional profiling and overlook organelle structure, a key indicator of metabolism and stress. We developed spatial Organellomics (sOrganellomics), an imaging workflow that integrates automated segmentation with machine learning to classify and spatially map cell states from multi-organelle signatures. In liver and pancreas, these signatures distinguished broad cellular classes. In liver, sOrganellomics revealed that zonal position did not fully explain organelle-defined hepatocyte categories. Instead, hepatocytes formed intermixed communities within canonical zones, supporting a refined subzonal diversity model. Nutritional stress reshaped this organization. Intravital imaging linked fasting-induced organelle remodeling with altered mitochondrial membrane potential in vivo, supporting multi-organelle architecture as a structural readout of tissue adaptation.