(PQ5) Role of Mitochondrial Division in Cancer Biology

 描述（由申请人提供）：线粒体生物学对人类癌症的影响是广泛的，因为这些细胞器是代谢、增殖和凋亡的关键调节剂。事实上，线粒体畸变在多种癌症类型中很常见-不仅线粒体功能障碍与疾病发病机制相关，而且异常的线粒体也对化疗成功产生负面影响。在细胞内，线粒体稳态通过称为“线粒体动力学”的过程来维持，这对于线粒体基因组完整性、有效ATP生成、管理ROS和线粒体代谢物的快速分布是必不可少的。线粒体动力学是由两种相反力量的累积性质引起的：线粒体分裂和线粒体融合。我的团队最近发表的工作表明：（1）线粒体分裂在RAS转化的鼠细胞和在MAPK途径内具有突变的人癌细胞系中长期增强，（2）线粒体分裂机制对于细胞转化是必需的，（3）抑制致癌MAPK信号传导的靶向治疗关闭线粒体分裂机制，和（4）慢性线粒体分裂足以引发线粒体功能障碍和癌细胞代谢。几十年来，已经描述了癌症中mtDNA突变和线粒体功能障碍的存在，但驱动这些变化的分子机制及其对癌症生物学的影响仍然是推测性的。虽然其他人和我们确定线粒体分裂是癌症相关线粒体功能障碍所必需的，并且是致癌MAPK通路抑制剂的靶向，但对线粒体分裂，线粒体功能障碍和癌细胞存活的分子机制知之甚少。我们假设致癌MAPK信号传导诱导慢性线粒体片段化，这支持线粒体基因组突变和随后线粒体网络内的功能异质性。这个项目是在多年的努力之后出现的，以确定线粒体分裂如何有助于癌症生物学， 我们提出了三个相辅相成的具体目标。目标1：确定慢性线粒体分裂是黑色素细胞中癌症相关mtDNA突变和随后线粒体功能障碍的原因。目标二：证明慢性线粒体分裂诱导的mtDNA突变与线粒体异质性、致瘤潜力和代谢可塑性有关。目的3：揭示慢性线粒体分裂在细胞和组织的致癌转化中的广泛需求。这些目标将通过使用下一代mtDNA测序、最先进的线粒体功能测定和代谢组学方法来实现。总之，本申请的结果将揭示：（1）慢性线粒体分裂允许线粒体DNA突变、线粒体功能障碍和肿瘤发生;和（2）概念验证证据表明，靶向慢性线粒体分裂的药物可以提供预防和治疗癌症的治疗潜力。

 DESCRIPTION (provided by applicant): The impact of mitochondrial biology on human cancers is broad because these organelles are critical regulators of metabolism, proliferation, and apoptosis. Indeed, mitochondrial aberrations are common in multiple cancer types --- not only do mitochondrial dysfunctions correlate with disease pathogenesis, but aberrant mitochondria also negatively impact upon chemotherapeutic success. Within a cell, mitochondrial homeostasis is maintained by a process referred to as "mitochondrial dynamics", which is essential for mitochondrial genome integrity, efficient ATP generation, managing ROS, and the rapid distribution of mitochondrial metabolites. Mitochondrial dynamics result from the cumulative nature of two opposing forces: mitochondrial division and mitochondrial fusion. Recent published work from my group demonstrated: (1) mitochondrial division is chronically enhanced in RAS-transformed murine cells and human cancer lines harboring mutations within the MAPK pathway, (2) the mitochondrial division machinery is essential for cellular transformation, (3) targeted therapies that inhibit oncogenic MAPK signaling turn off the mitochondrial division machinery, and (4) chronic mitochondrial division is sufficient to initiate mitochondrial dysfunction and cancer cell metabolism. For decades, the presence of mtDNA mutations and mitochondrial dysfunction in cancer has been described, but the molecular mechanisms that drive these changes and their impact on cancer biology remain speculative. While others and we identified that mitochondrial division is requisite to cancer-associated mitochondrial dysfunction and is targeted by oncogenic MAPK pathway inhibitors, the molecular mechanisms linking mitochondrial division, mitochondrial dysfunction, and cancer cell survival are poorly understood. We hypothesize that oncogenic MAPK signaling induces chronic mitochondrial fragmentation, which supports mutation of the mitochondrial genome and subsequent functional heterogeneity within the mitochondrial network. This project emerged following years of effort to identify how mitochondrial division contributes to cancer biology, and we propose three complementary specific aims. Aim 1: Establish that chronic mitochondrial division is responsible for cancer-associated mtDNA mutations and subsequent mitochondrial dysfunction in melanocytes. Aim 2: Demonstrate that chronic mitochondrial division induced mtDNA mutations link mitochondrial heterogeneity, tumorigenic potential, and metabolic plasticity. Aim 3: Reveal the broad requirement for chronic mitochondrial division in oncogenic transformation of cells and tissues. These aims will be achieved by using next-generation mtDNA sequencing, state-of-the-art mitochondrial function assays, and metabolomics approaches. Together, the results of this application will reveal that: (1) chronic mitochondrial division is permissive for mtDNA mutations, mitochondrial dysfunction, and tumorigenesis; and (2) proof-of- concept evidence that pharmacologically targeting chronic mitochondrial division may provide therapeutic potential to prevent and treat cancer.