(PQ5) Contribution of mitochondrial pathways to metabolic heterogeneity in molecular subtypes of Diffuse Large B Cell Lymphoma

项目总结 线粒体网络是由融合和裂变动力学形成的，最终影响线粒体 利用燃料的能力。我们最近对弥漫性大B细胞淋巴瘤(DLBCL)代谢回路的剖析 DLBCL亚型线粒体结构和生化网络的异质性 燃料利用的模式。OXPHOS-DLBCL显示线粒体碎片净增加，并依赖于 线粒体脂肪酸氧化(FAO)对B细胞受体(BCR)非依赖性生存和增殖的影响 发信号。这与非OxPhos/Warburg类型的DLBCL不同，后者依赖BCR，依赖糖酵解 并连接了线粒体网络。重要的是，阻断OxPhos-DLBCL中的碎片可以减少 线粒体FA利用能力，但不改变其他燃料的消耗。 上述观察表明，在促进线粒体处理的过程中，对片段化有特殊的要求。 Fas，并将线粒体形态异质性与DLBCL的燃料选择和代谢专门化联系起来 子类型。针对RFA-CA-17-017 PQ5，拟议的研究审查了这些机制和 这种联系的后果及其与肿瘤发生的相关性。在目标1中，我们将定义机械论 OxPhos-VS BCR-DLBCL中线粒体断裂净增加的决定因素，包括变化 在单个线粒体水平上的融合和裂变率以及线粒体形成蛋白的变化。 我们还将探讨线粒体断裂改变对生长和生存的长期影响。 体外和体内DLBCL亚型的比较。在目标2中，我们将了解线粒体的后果 燃料利用总体上、特别是粮农组织的碎片化。碳追踪和碳追踪的结合 将进行生化研究，以确定线粒体FA的潜在调节机制 OxPhos-DLBCL中线粒体碎裂的处理。在目标3中，我们将确定线粒体是如何 BCR启动的信号调节了结构和燃料代谢，并探讨了它们之间的相关性 Bcr-DLBCL对临床相关bcr抑制剂敏感性的线粒体通路。 总之，这些研究可以提供重要的概念进步和机制洞察 DLBCL的线粒体形态特化与支持肿瘤生长的燃料利用交织在一起。

PROJECT SUMMARY The mitochondrial network is shaped by fusion and fission dynamics that ultimately influence the mitochondrial capacity to utilize fuels. Our recent dissection of metabolic circuits in diffuse large B-cell lymphoma (DLBCL) has identified heterogeneity of mitochondrial architecture and biochemical networks in DLBCL subtypes with distinct patterns of fuel utilization. OxPhos-DLBCLs show a net increase in mitochondrial fragmentation and rely on mitochondrial fatty acid oxidation (FAO) for survival and proliferation independent of B-cell receptor (BCR) signaling. This is distinct from non-OxPhos/Warburg type DLBCLs that are BCR-dependent, rely on glycolysis and have connected mitochondrial network. Importantly, blocking fragmentation in OxPhos-DLBCLs reduces mitochondrial FA utilization capacity but does not alter consumption of other fuels. The above observations indicate a specific requirement for fragmentation in facilitating mitochondrial handling of FAs, and link mitochondrial morphologic heterogeneity to fuel choice and metabolic specialization in DLBCL subtypes. In response to RFA-CA-17-017 PQ5, the proposed studies examine the mechanisms and consequences of this link and its relevance to tumorigenesis. In Aim 1, we will define the mechanistic determinants of the net increase in mitochondrial fragmentation in OxPhos- vs BCR-DLBCLs, including changes in fusion and fission rates at the level of individual mitochondria and alterations in mitochondria-shaping proteins. We will also address the long-term consequences of altered mitochondrial fragmentation in growth and survival of DLBCL subtypes in vitro and in vivo. In Aim 2, we will learn about the consequence of mitochondrial fragmentation for fuel utilization in general and FAO in particular. A combination of carbon tracing and biochemical studies will be undertaken to determine the mechanisms underlying regulation of mitochondrial FA handling by mitochondrial fragmentation in OxPhos-DLBCLs. In Aim 3, we will determine how mitochondrial architecture and fuel metabolism are modulated by BCR-initiated signals, and probe the relevance of these mitochondrial pathways to the sensitivity of BCR-DLBCLs to clinically-relevant BCR inhibitors. Together, these studies can provide important conceptual advancement and mechanistic insights into how the mitochondrial morphologic specializations in DLBCLs are intertwined with fuel utilization to support tumor growth.