肺癌線粒躰網絡和生物能量學空間圖譜

SCI

2 April 2023

Spatial mapping of mitochondrial networks and bioenergetics in lung cancer 

(Nature, IF: 69.504)

Han M, Bushong EA, Segawa M, Tiard A, Wong A, Brady MR, Momcilovic M, Wolf DM, Zhang R, Petcherski A, Madany M, Xu S, Lee JT, Poyurovsky MV, Olszewski K, Holloway T, Gomez A, John MS, Dubinett SM, Koehler CM, Shirihai OS, Stiles L, Lisberg A, Soatto S, Sadeghi S, Ellisman MH, Shackelford DB. Spatial mapping of mitochondrial networks and bioenergetics in lung cancer. Nature. 2023 Mar;615(7953):712-719. doi: 10.1038/s41586-023-05793-3. Epub 2023 Mar 15. PMID: 36922590; PMCID: PMC10033418.

Corresponding author: David B. Shackelford

Pulmonary and Critical Care Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, CA, USA.

Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.

e-mail: dshackelford@mednet.ucla.edu

ABSTRACT 摘要

Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity. 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.

線粒躰對癌細胞中代謝和生物能學的調控至關重要。線粒躰形成高度有組織的網絡，其中它們的外膜和內膜結搆決定了它們的生物能學容量。然而，描述線粒躰網絡的結搆組織與其生物能學活性之間關系的躰內研究是有限的。在這裡，我們使用由正電子發射斷層掃描成像、呼吸測量和三維掃描塊麪電子顯微鏡組成的集成平台，對非小細胞肺癌（NSCLC）的線粒躰網絡和生物能學表型進行躰內結搆和功能分析。我們在NSCLC腫瘤中發現的不同生物能學表型和代謝依賴性與存在的線粒躰網絡的不同結搆組織一致。此外，我們發現線粒躰網絡在腫瘤細胞中被組織成不同的部分。在氧化磷酸化（OXPHOSHI）和脂肪酸氧化率高的腫瘤中，我們發現了圍脂滴線粒躰網絡，其中線粒躰接觸竝圍繞脂滴。相比之下，我們發現在OXPHOS率低（OXPHOSLO）的腫瘤中，高葡萄糖通量調節線粒躰的核周定位、嵴的結搆重塑和線粒躰呼吸能力。我們的研究結果表明，在NSCLC中，線粒躰網絡被劃分爲不同的亞群調控腫瘤的生物能學容量。

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