Journal Article

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

Stiles, Linsey, Gomez, Adrian, Shirihai, Orian, Abdelhady, Gihad, Stout, David, Schmid, Ernst, Jones, Anthony, Holloway, Travis, Sadeghi, Saman, Dabir, Deepa V., Dubinett, Steven M., Christofk, Heather, Li, Rui, Momcilovic, Milica, Bailey, Sean T., Shackelford, David B., Waldmann, Christopher M., Lee, Jason T., Fishbein, Michael C., Koehler, Carla M.

2019

Overview

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 ATP 1 . 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-[ 18 F]fluorobenzyl-triphenylphosphonium ( 18 F-BnTP) 4 . By using PET imaging of 18 F-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 18 F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours. A positron emission tomography imaging tracer is developed to image mitochondrial function in vivo, and application of this tracer to a mouse model of lung cancer identifies distinct functional mitochondrial heterogeneity between tumour cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 13/51 / 13/95 / 14 / 59 / 59/78 / 631/67/1612/1350 / 631/67/2321 / 631/67/2327 / 64/110 / A549 Cells / Animal models / Animals / Apoptosis / Bioenergetics / Biotechnology / Carcinoma, Non-Small-Cell Lung - diagnostic imaging / Carcinoma, Non-Small-Cell Lung - physiopathology / Cell culture / Chain drives / Development and progression / Electron transport / Electron transport chain / Energy metabolism / Fluorine isotopes / Health aspects / Heterogeneity / Humanities and Social Sciences / Humans / In vivo methods and tests / Lung cancer / Lung cancer, Non-small cell / Lung diseases / Lung Neoplasms - diagnostic imaging / Lung Neoplasms - physiopathology / Medical imaging / Membrane potential / Membrane Potential, Mitochondrial / Membrane potentials / Membranes / Metabolism / Metabolites / Mice / Mice, Transgenic / Mitochondria / Mitochondrial membranes / multidisciplinary / Non-small cell lung carcinoma / Organophosphorus Compounds / Oxidative metabolism / Oxidative phosphorylation / PET imaging / Phosphorylation / Physiological aspects / Positron emission / Positron emission tomography / Potential gradient / Radioactive tracers / Regulators / Science / Science (multidisciplinary) / Synthesis / Tomography / Tumorigenesis / Tumors / Xenografts