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. KoehlerOrian S. Shirihai, Linsey Stiles, Aaron Lisberg, Stefano Soatto, Saman Sadeghi, Mark H. Ellisman, David B. Shackelford

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)712-719
Number of pages8
JournalNature
Volume615
Issue number7953
DOIs
StatePublished - Mar 23 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'Spatial mapping of mitochondrial networks and bioenergetics in lung cancer'. Together they form a unique fingerprint.

Cite this