CIL:54862, Mouse lung tumor, Lung tumor tissue. In Cell Image Library

In this study we employed a voltage sensitive, positron emission tomography (PET) tracer known as fluorobenzyl triphenylphosphonium (FBnTP) (<i>Momcilovic et al., (2019) Nature</i>), to profile mitochondrial bioenergetics in autochthonous mouse models of lung cancer. By coupling the glucose analog PET tracer, fluoro-2-deoxy-D-glucose (F-FDG), we identified two distinct tumor sub-populations – lung adenocarcinomas (LUAD), characterized by FBnTP^HI and F-FDG^LO uptake and lung squamous cell carcinomas (LUSC), characterized by FBnTP^LO and F-FDG^HI uptake. The structural organization of the mitochondria directly impacts the bioenergetic capacity of both normal and tumor cells. We therefore explored the architecture of mitochondria in in vivo lung tumors with different PET signatures using 3D serial block-face electron microscopy (SBEM) in order to understand how mitochondrial networks impact cellular respiration and metabolism. Pairing PET imaging with 3D SBEM enabled us to functionally image mitochondria activity in whole lung tumors followed by mapping of mitochondrial ultrastructures down to the resolution of cristae. Our ultrastructure analysis of mitochondrial networks in LUAD and LUSC identified distinct mitochondrial subpopulations exist that carry equally distinct bioenergetic phenotypes. We discovered that mitochondrial networks in LUADs were distinguished by the predominance of lipid droplet bound mitochondrial subpopulations that support cellular respiration. In contrast, we identified in LUSCs that glucose flux is a key regulator of cristae remodeling and the cellular localization of mitochondrial networks. Structure-and-function studies defining the relationship between mitochondrial architecture and metabolic dependencies may hold promise as strategies to profile metabolic liabilities unique to lung cancer subtypes. We anticipate that coupling PET imaging with 3D SBEM will have dynamic applications beyond that of lung cancer and enrich our understanding of how mitochondrial bioenergetics impact human disease.