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Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.

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Han, Mingqi 
Bushong, Eric A 
Tiard, Alexandre 
Wong, Alex 


Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells1. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity2,3. However, in vivo studies delineating the relationship between the structural organization of mitochondrial networks and their bioenergetic activity have been limited. Here we present an in vivo structural and functional analysis of mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer (NSCLC) using an integrated platform consisting of positron emission tomography imaging, respirometry and three-dimensional scanning block-face electron microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we identified in NSCLC tumours align with distinct structural organization of mitochondrial networks present. Further, we discovered that mitochondrial networks are organized into distinct compartments within tumour cells. In tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid oxidation, we identified peri-droplet mitochondrial networks wherein mitochondria contact and surround lipid droplets. By contrast, we discovered that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated perinuclear localization of mitochondria, structural remodelling of cristae and mitochondrial respiratory capacity. Our findings suggest that in NSCLC, mitochondrial networks are compartmentalized into distinct subpopulations that govern the bioenergetic capacity of tumours.


Acknowledgements: We thank C. Zamilpa, D. Abeydeera and J. Collins, at UCLA’s Crump Imaging Technology Center, for assistance with PET–CT imaging of the mice. We thank the Translational Pathology Core Laboratory at UCLA’s DGSOM for assistance with tumour sample preparation and processing. We also thank M. McCaffery for assistance with electron microscopy imaging on in vitro-cultured cells and J. Castillo for assistance with graphics. This research was supported by the NIH National Center for Advancing Translational Science UCLA CTSI grant number UL1TR001881. D.B.S. was supported by the UCLA CTSI KL2 Translational Science Award grant number KL2TR001882 at the UCLA David Geffen School of Medicine, the UCLA Jonsson Comprehensive Cancer Center grant P30 CA016042, NIH/NCI R01 CA208642-01, American Cancer Society grant numbers RSG-16-234-01-TBG and MBG-19-172-01-MBG, and Department of Defense LCRP grant numbers W81XWH-13-1-0439 and W81XWH-18-1-0295. M.H. was supported by NIH/NCI R01 CA208642-01. A.L. was supported by grant NIH-NCI K08 CA245249-01A1 and a LUNGevity 2019 Career Development Award. M. Momcilovic was supported by American Cancer Society grant numbers RSG-16-234-01-TBG and MBG-19-172-01-MBG. A.G. was supported by an NIH/NCI R01 CA208642-01 diversity supplement. J.T.L. was supported by NIH/NCI P30 CA016042. D.M.W. is supported by EMBO long-term fellowship ALTF 828-2021. This research was supported by the Joyce and Saul Brandman Fund for Medical Research. We extend our heartfelt thanks and appreciation to the Scott family and the Carrie Strong Foundation as well as B. and D. Goldfarb for their generous support.


Humans, Carcinoma, Non-Small-Cell Lung, Energy Metabolism, Fatty Acids, Glucose, Lipid Droplets, Lung Neoplasms, Microscopy, Electron, Mitochondria, Oxidative Phosphorylation, Phenotype, Positron-Emission Tomography

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