(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:
- 金额:$ 35.12万
- 依托单位:
- 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:
- 关键词:AddressApoptosisBiological AssayBiological ModelsBiologyCancer BiologyCell SurvivalCell modelCellsChronicDataDevelopmentDiseaseDrosophila genusFunctional disorderGenerationsGenetic ScreeningGenomicsHeterogeneityHomeostasisHumanIn VitroLinkLiteratureMAP Kinase GeneMalignant NeoplasmsMetabolicMetabolismMitochondriaMitochondrial DNAMolecularMusMutationNatureOncogenesOncogenicOrganellesPathogenesisPathway interactionsPharmacologyPhenotypeProcessPublishingRNA InterferenceRegulationRoleScreening ResultSignal TransductionTherapeuticTissuesWorkcancer cellcancer typecell transformationcohortgenome integrityin vivoinhibitor/antagonistinnovationmelanocytemelanomametabolomicsmetaplastic cell transformationmitochondrial DNA mutationmitochondrial dysfunctionmitochondrial genomemitochondrial metabolismnext generationnoveloutcome forecastpreventpublic health relevanceresponsesuccesstargeted treatmenttumor metabolismtumorigenesistumorigenic
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(由适用提供):线粒体生物学对人类癌症的影响很广,因为这些细胞器是代谢,增殖和凋亡的关键调节剂。实际上,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理相关,而且线粒体异常对化学治疗成功也产生负面影响。在细胞中,线粒体稳态通过称为“线粒体动力学”的过程维持,这对于线粒体基因组完整性,有效的ATP生成,管理ROS和线粒体代谢物的快速分布至关重要。线粒体动力学是由于两种相对力的累积性而产生的:线粒体分裂和线粒体融合。我小组的最新发表的工作证明了:(1)线粒体分裂在RAS转换的鼠细胞和MAPK途径内具有突变的人类癌线中长期增强,(2)线粒体分裂机械对于细胞转化至关重要线粒体分裂足以启动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,但是驱动这些变化及其对癌症生物学的影响的分子机制仍然是推测性的。虽然其他人和我们确定线粒体分裂是与癌症相关的线粒体功能障碍需要的,并且是由致癌的MAPK途径抑制剂靶向的,但联系线粒体分裂,线粒体功能障碍和癌细胞存活的分子机制已连接。我们假设致癌的MAPK信号传导诱导慢性线粒体碎片,从而支持线粒体基因组的突变以及线粒体网络中随后的功能异质性。经过多年的努力,出现了该项目,以确定线粒体分裂如何对癌症生物学做出贡献,并且
我们提出了三个完整的特定目标。目标1:确定慢性线粒体分裂负责与癌症相关的mtDNA突变以及随后的黑素细胞中线粒体功能障碍。 AIM 2:证明慢性线粒体诱导的mtDNA突变连接线粒体异质性,致瘤性潜力和代谢可塑性。 AIM 3:揭示了细胞和组织致癌转化中慢性线粒体分裂的广泛要求。这些目标将通过使用下一代MTDNA测序,最新的线粒体功能测定和代谢组学方法来实现。总之,该应用的结果将表明:(1)慢性线粒体分裂允许mtDNA突变,线粒体功能障碍和肿瘤发生; (2)概念验证证据证明,在药理学上靶向慢性线粒体分裂可能会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:
- 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:
- 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:
- 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
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Jerry Edward Chipuk其他文献
Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis
- DOI:
10.1016/j.devcel.2024.09.004 - 发表时间:
2024-10-07 - 期刊:
- 影响因子:
- 作者:
Jesminara Khatun;Jesse D. Gelles;Jerry Edward Chipuk - 通讯作者:
Jerry Edward Chipuk
Jerry Edward Chipuk的其他文献
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{{ truncateString('Jerry Edward Chipuk', 18)}}的其他基金
Chronic Mitochondrial Division and Melanoma: Mechanism, Prognosis, and Therapy
慢性线粒体分裂和黑色素瘤:机制、预后和治疗
- 批准号:
10666459 - 财政年份:2022
- 资助金额:
$ 35.12万 - 项目类别:
Chronic Mitochondrial Division and Melanoma: Mechanism, Prognosis, and Therapy
慢性线粒体分裂和黑色素瘤:机制、预后和治疗
- 批准号:
10464554 - 财政年份:2022
- 资助金额:
$ 35.12万 - 项目类别:
(PQ5) Role of Mitochondrial Division in Cancer Biology
(PQ5) 线粒体分裂在癌症生物学中的作用
- 批准号:
9256448 - 财政年份:2016
- 资助金额:
$ 35.12万 - 项目类别:
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