MITOCHONDRIAL FISSION AND NEURODEGENERATION

线粒体裂变和神经变性

• 批准号: 7601037
• 负责人: Ella R Bossy-Wetzel
• 金额: $ 3.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601037
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Apoptotic; Biogenesis; Brown Fat; Cell Death; Cell physiology; Cells; Computer Retrieval of Information on Scientific Projects Database; Condition; Cytoplasm; Electron Microscope; Electron Microscopy; Equilibrium; Functional disorder; Funding; Future; Glutamate Receptor; Grant; Guanosine Triphosphate Phosphohydrolases; Huntington Disease; Injury; Institution; Investigation; Localized; Mediating; Membrane Potentials; Mitochondria; Mitogens; Morphology; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neurotransmitters; Nitric Oxide; Normal Cell; Numbers; Optics; Organelles; Parkinson Disease; Peroxonitrite; Phosphotransferases; Physiological; Physiological Processes; Play; Process; Property; Receptor Activation; Research; Research Personnel; Resources; Respiration; Role; Signal Transduction Pathway; Site; Source; Stress; Stroke; Study models; Tissues; United States National Institutes of Health; Work; mitochondrial membrane; neuron loss; neurotoxic; size; tomography

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nitric oxide (NO) plays a pivotal role in normal cell physiology. In brown fat tissue NO regulates mitochondrial biogenesis. In the central nervous system (CNS), NO functions as an important neurotransmitter, but when overproduced by excessive glutamate receptor activation, NO converts to peroxynitrite (ONOO-), a highly reactive, neurotoxic radical. NO-mediated neuronal injury is implicated in several neurodegenerative disorders, including stroke, Parkinsons disease, Alzheimers disease, Huntingtons disease, and ALS. NO/ONOO- inhibits mitochondrial respiration and ONOO- liberates Zn2+ from endogenous stores, which in turn triggers further mitochondrial injury. Besides these properties, NO/ONOO- activates signal transduction pathways of mitogen activated kinases, which can participate in neuronal demise. The mechanism underlying nitrosative stress-mediated neuronal cell death is not fully understood, but mitochondrial injury appears to be central. Thus a better understanding of the mechanism underlying mitochondrial injury during neurodegeneration is required. Electron microscopy and electron microscope tomography can help elucidate mitochondrial injury in the neurodegeneration models we are studying. Mitochondria are dynamic organelles, undergoing frequent fission and fusion. These opposing processes are choreographed by a conserved group of large GTPases. Their balanced activities dictate mitochondrial morphology, size, and number. Drp1, which is found in the cytoplasm and on mitochondria, has emerged as key mitochondrial fission factor. Upon activation by an unknown mechanism, Drp1 accumulates at mitochondria and preferentially localizes to future fission sites. Conversely, mitochondrial fusion is regulated by large GTPases, such as Mitofusin1 and 2 (Mfn1 and 2) and optic atrophy1 (OPA1). Mitochondrial fusion requires an intact mitochondrial membrane potential (DYm). Loss of either Mfn1, 2 or OPA1 results in mitochondrial fission and cellular dysfunction. Mitochondrial division is a normal physiological process; however, extensive mitochondrial division or fission can occur under patho-physiological conditions. Evidence has emerged indicating that mitochondrial fission plays an active part in apoptotic cell death. The work with Dr. Perkins at NCMIR principally involves the investigation of mitochondrial fission in cells and tissues.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 一氧化氮（NO）在正常细胞生理中起关键作用。在棕色脂肪组织中，没有调节线粒体生物发生。在中枢神经系统（CNS）中，无作为重要的神经递质，但是当过量谷氨酸受体激活过度生产时，没有转化为过氧亚硝酸盐（ONOO-），这是一种高度反应性，神经毒性的自由基。 NO介导的神经元损伤与几种神经退行性疾病有关，包括中风，帕金森氏病，阿尔茨海默氏病，亨廷顿氏病和ALS。没有/onoo-抑制线粒体呼吸，并从内源商店中解放了Zn2+，这反过来又触发了线粒体损伤。除这些特性外，无/onoo激活有丝分裂原激活激酶的信号转导途径，可以参与神经元灭绝。亚硝化应激介导的神经元细胞死亡的基础机制尚不完全了解，但线粒体损伤似乎是中心的。因此，需要更好地了解神经退行性过程中线粒体损伤的机制。 电子显微镜和电子显微镜断层扫描可以帮助阐明我们正在研究的神经变性模型中的线粒体损伤。 线粒体是动态细胞器，经常进行裂变和融合。这些相反的过程由一组保守的大GTPases编排。他们平衡的活动决定了线粒体形态，大小和数字。在细胞质和线粒体上发现的DRP1已成为关键的线粒体裂变因子。通过未知机制激活后，DRP1在线粒体上积聚，优先将其定位于将来的裂变位点。相反，线粒体融合受大型GTPases（例如Mitofusin1和2（MFN1和2）和Optic Atrophy1（OPA1）的调节。线粒体融合需要完整的线粒体膜电位（DYM）。 MFN1、2或OPA1的丧失会导致线粒体裂变和细胞功能障碍。线粒体分裂是正常的生理过程。但是，在病原生理条件下可能发生广泛的线粒体分裂或裂变。有证据表明线粒体裂变在凋亡细胞死亡中起积极作用。与珀金斯博士在NCMIR的工作主要涉及对细胞和组织中线粒体裂变的研究。