MITOCHONDRIAL FISSION AND NEURODEGENERATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 一氧化氮（NO）在正常细胞生理中起着关键作用。在棕色脂肪组织中，NO调节线粒体生物合成。在中枢神经系统（CNS）中，NO作为一种重要的神经递质发挥作用，但是当过量的谷氨酸受体激活而过量产生时，NO转化为过氧亚硝酸盐（ONOO-），一种高度反应性的神经毒性自由基。NO介导的神经元损伤与多种神经退行性疾病有关，包括中风、帕金森病和帕金森病。老年痴呆症亨廷顿舞蹈病的疾病和ALS。NO/ONOO-抑制线粒体呼吸，ONOO-从内源性储存中释放Zn 2+，这反过来又引发进一步的线粒体损伤。除了这些特性，NO/ONOO-激活丝裂原激活激酶的信号转导途径，其可以参与神经元死亡。亚硝化应激介导的神经元细胞死亡的机制尚未完全了解，但线粒体损伤似乎是中心。因此，需要更好地理解神经退行性变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。 线粒体是一种动态的细胞器，经常发生分裂和融合。这些相反的过程是由一组保守的大GTP酶编排的。它们的平衡活动决定了线粒体的形态、大小和数量。Drp 1存在于细胞质和线粒体中，已成为关键的线粒体分裂因子。通过一种未知的机制激活后，Drp 1在线粒体中积累，并优先定位于未来的裂变位点。相反，线粒体融合由大的GTP酶调节，如Mitofusin 1和2（Mfn 1和2）和视神经萎缩1（OPA 1）。线粒体融合需要完整的线粒体膜电位（DYm）。Mfn 1、2或OPA 1的缺失导致线粒体分裂和细胞功能障碍。线粒体分裂是一个正常的生理过程;然而，广泛的线粒体分裂或裂变可以发生在病理生理条件下。有证据表明线粒体分裂在凋亡性细胞死亡中起着积极的作用。Perkins在NCMR的工作主要涉及细胞和组织中线粒体分裂的研究。

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.