In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer

Mitochondria are essential regulators of cellular energy and metabolism, and have a crucial role in sustaining the growth and survival of cancer cells. A central function of mitochondria is the synthesis of ATP by oxidative phosphorylation, known as mitochondrial bioenergetics. Mitochondria maintain oxidative phosphorylation by creating a membrane potential gradient that is generated by the electron transport chain to drive the synthesis of ATP¹. Mitochondria are essential for tumour initiation and maintaining tumour cell growth in cell culture and xenografts^2,3. However, our understanding of oxidative mitochondrial metabolism in cancer is limited because most studies have been performed in vitro in cell culture models. This highlights a need for in vivo studies to better understand how oxidative metabolism supports tumour growth. Here we measure mitochondrial membrane potential in non-small-cell lung cancer in vivo using a voltage-sensitive, positron emission tomography (PET) radiotracer known as 4-[¹⁸F]fluorobenzyl-triphenylphosphonium (¹⁸F-BnTP)⁴. By using PET imaging of ¹⁸F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse models of lung cancer, and find distinct functional mitochondrial heterogeneity within subtypes of lung tumours. The use of ¹⁸F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours.