Spatial mapping of mitochondrial networks and bioenergetics in lung cancer

Mingqi Han, Eric A. Bushong, Mayuko Segawa, Alexandre Tiard, Alex Wong, Morgan R. Brady, Milica Momcilovic, Dane M. Wolf, Ralph Zhang, Anton Petcherski, Matthew Madany, Shili Xu, Jason T. Lee, Masha V. Poyurovsky, Kellen Olszewski, Travis Holloway, Adrian Gomez, Maie St. John, Steven M. Dubinett, Carla M. Koehler, Orian S. Shirihai, Linsey Stiles, Aaron Lisberg, Stefano Soatto, Saman Sadeghi, Mark H. Ellisman and David B. Shackelford ()
Additional contact information
Mingqi Han: University of California Los Angeles (UCLA)
Eric A. Bushong: University of California San Diego (UCSD)
Mayuko Segawa: University of Cambridge
Alexandre Tiard: UCLA
Alex Wong: Yale University
Morgan R. Brady: University of California Los Angeles (UCLA)
Milica Momcilovic: University of California Los Angeles (UCLA)
Dane M. Wolf: University of Cambridge
Ralph Zhang: University of California Los Angeles (UCLA)
Anton Petcherski: DGSOM UCLA
Matthew Madany: University of California San Diego (UCSD)
Shili Xu: UCLA
Jason T. Lee: UCLA
Masha V. Poyurovsky: Kadmon Corporation
Kellen Olszewski: Kadmon Corporation
Travis Holloway: UCLA
Adrian Gomez: UCLA
Maie St. John: UCLA
Steven M. Dubinett: University of California Los Angeles (UCLA)
Carla M. Koehler: UCLA
Orian S. Shirihai: DGSOM UCLA
Linsey Stiles: DGSOM UCLA
Aaron Lisberg: UCLA
Stefano Soatto: UCLA
Saman Sadeghi: McMaster University
Mark H. Ellisman: University of California San Diego (UCSD)
David B. Shackelford: University of California Los Angeles (UCLA)

Nature, 2023, vol. 615, issue 7953, 712-719

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-05793-3

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