(PQ5) Role of Mitochondrial Division in Cancer Biology

(PQ5) 线粒体分裂在癌症生物学中的作用

基本信息

批准号：
9888358
负责人：
Jerry Edward Chipuk
金额：
$ 35.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-06 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888358
关键词：
Address Apoptosis Biological Assay Biological Models Biology Cancer Biology Cell Survival Cell model Cells Chronic Data Development Disease Drosophila genus Functional disorder Generations Genetic Screening Genomics Heterogeneity Homeostasis Human In Vitro Link Literature MAP Kinase Gene Malignant Neoplasms Metabolic Metabolism Mitochondria Mitochondrial DNA Molecular Mus Mutation Nature Oncogenes Oncogenic Organelles Pathogenesis Pathway interactions Pharmacology Phenotype Process Publishing RNA Interference Regulation Role Screening Result Signal Transduction Therapeutic Tissues Work cancer cell cancer type cell transformation cohort genome integrity in vivo inhibitor/antagonist innovation melanocyte melanoma metabolomics metaplastic cell transformation mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mitochondrial metabolism next generation novel outcome forecast prevent public health relevance response success targeted treatment tumor metabolism tumorigenesis tumorigenic

项目摘要

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.

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，因为这些细胞器是新陈代谢、增殖和细胞凋亡的关键调节因子。事实上，线粒体畸变在多种癌症类型中很常见——不仅与线粒体功能障碍相关。线粒体稳态与疾病发病机制有关，但异常的线粒体也会对化疗的成功产生负面影响，在细胞内，线粒体稳态是通过称为“线粒体动力学”的过程来维持的，这对于化疗至关重要。线粒体基因组完整性、有效的 ATP 生成、ROS 和线粒体代谢物的快速分布是由两种相反力量的累积性质造成的：线粒体分裂和线粒体融合，我的团队最近发表的工作证明：（1）线粒体分裂。在 RAS 转化的小鼠细胞和含有 MAPK 途径突变的人类癌细胞系中长期增强，(2) 线粒体分裂机制对于细胞转化至关重要，(3) 抑制致癌 MAPK 信号传导的靶向治疗关闭线粒体分裂机制，以及（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，人们已经描述了癌症中线粒体DNA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。虽然我们和其他人都认为线粒体分裂是癌症相关线粒体功能障碍所必需的，并且是通过致癌 MAPK 途径抑制剂实现的，但将线粒体分裂、线粒体功能障碍和癌细胞存活联系起来的分子机制仍然是推测性的。我们对致癌 MAPK 信号传导诱导慢性线粒体断裂进行研究，从而支持线粒体基因组的突变以及线粒体网络内随后的功能异质性，该项目是在多年努力确定线粒体分裂如何促进癌症生物学之后出现的。我们提出了三个互补的具体目标目标 1：确定慢性线粒体分裂是导致黑色素细胞中癌症相关 mtDNA 突变和随后的线粒体功能障碍的原因目标 2：证明慢性线粒体诱导的 mtDNA 分裂与线粒体异质性、致瘤潜力和代谢有关。目标 3：揭示细胞和组织致癌转化中线粒体慢性分裂的广泛要求。这些目标将通过使用下一代 mtDNA 测序来实现。最先进的线粒体功能测定和代谢组学方法共同表明：（1）慢性线粒体分裂可能导致线粒体DNA突变、线粒体功能障碍和肿瘤发生；（2）概念证据表明，针对慢性线粒体分裂的药理学可能提供预防和治疗癌症的治疗潜力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Jerry Edward Chipuk: A powerhouse for mitochondrial biology.

DOI：
10.1083/jcb.201807034
发表时间：
2018-08-06
期刊：
The Journal of cell biology
影响因子：
0
作者：
O'Donnell MA;Infarinato N
通讯作者：
Infarinato N

Mitochondrial Fission in Human Diseases.

DOI：
10.1007/164_2016_38
发表时间：
2017
期刊：
Handbook of experimental pharmacology
影响因子：
0
作者：
Serasinghe MN;Chipuk JE
通讯作者：
Chipuk JE

Cell death through the ages: The ICDS 25th Anniversary Meeting.

DOI：
10.1111/febs.15252
发表时间：
2020-06
期刊：
The FEBS journal
影响因子：
0
作者：
Mohammed JN;Gelles JD;Rubio-Patiño C;Serasinghe MN;Trotta AP;Lockshin RA;Zakeri Z;Chipuk JE
通讯作者：
Chipuk JE