肺癌线粒体网络和生物能量学空间图谱

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.

线粒体对癌细胞中代谢和生物能学的调控至关重要。线粒体形成高度有组织的网络，其中它们的外膜和内膜结构决定了它们的生物能学容量。然而，描述线粒体网络的结构组织与其生物能学活性之间关系的体内研究是有限的。在这里，我们使用由正电子发射断层扫描成像、呼吸测量和三维扫描块面电子显微镜组成的集成平台，对非小细胞肺癌（NSCLC）的线粒体网络和生物能学表型进行体内结构和功能分析。我们在NSCLC肿瘤中发现的不同生物能学表型和代谢依赖性与存在的线粒体网络的不同结构组织一致。此外，我们发现线粒体网络在肿瘤细胞中被组织成不同的部分。在氧化磷酸化（OXPHOSHI）和脂肪酸氧化率高的肿瘤中，我们发现了围脂滴线粒体网络，其中线粒体接触并围绕脂滴。相比之下，我们发现在OXPHOS率低（OXPHOSLO）的肿瘤中，高葡萄糖通量调节线粒体的核周定位、嵴的结构重塑和线粒体呼吸能力。我们的研究结果表明，在NSCLC中，线粒体网络被划分为不同的亚群调控肿瘤的生物能学容量。

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