Spatial mapping of mitochondrial networks and bioenergetics in lung cancer

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.

Scalable droplet-based radiosynthesis of [18F]fluorobenzyltriphenylphosphonium cation ([18F]FBnTP) via a “numbering up” approach

“…The simplicity and speed of this synthesis method, along with improved yield and reduced precursor amount, will greatly facilitate further preclinical and clinical evaluation of [ 18 F]FBnTP for MPI or other applications, like lung cancer studies. 32,33 Moreover, this efficient droplet-based scale-up technique can readily be applied to prepare other radiotracers on demand, enabling quick and cost-effective production of various radiotracers for diverse applications. This work represents the first successful trial of scaling up the synthesis in a droplet microreactor by the numbering up technique.…”

18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity

“…The cells were then incubated overnight at 37 °C, 5% CO 2 . The medium was removed and replaced with preheated (37 °C) medium containing the mitochondrial staining MitoTracker solution (Thermo Fisher, M7510, a referenced method for measuring mitochondrial density − ) at 150 nM and then incubated for 30 min at 37 °C, 5% CO 2 . The cells were then rinsed 2× with PBS 0.1 M and fixed using preheated (37 °C) PFA 4% for 15 min at 37 °C.…”

PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity

“…Tumor-bearing mice were injected with 60 µCi of [ 18 F]-FDG (PETNET Solutions) or [ 18 F]-BnTP (prepared as previously described 107 through tail vein intravenous injections. Following a 60-minute unconscious uptake of the imaging tracer, mice were anesthetized with 2% vaporized isoflurane, and microPET (GSE183198), which were downloaded directly from the Gene Expression Omnibus (GEO).…”