Probing the Relationship Between Protein Kinase C and mTOR in Mitochondrial Function

线粒体功能障碍在病理上会导致许多无法治愈的疾病，如神经代谢 利氏综合症几乎肯定会导致儿童死亡。它还加剧了最晚的- 罹患癌症、阿尔茨海默氏症和心脏病等疾病。帮助满足未满足的新的医疗需求 防止这些疾病发生的治疗方法，Kaeberlein小组专注于阐明新的 线粒体疾病进展机制及有效药理研究进展 具有特定分子靶点的干预。为了做到这一点，我们利用领先的哺乳动物模型Leigh 综合征缺失电子传输链结构蛋白亚基NDUFS4。这些小鼠表现出严重的 神经退行性表型和过早死亡。我的团队最近发现了FDA批准的mTOR 抑制剂雷帕霉素可显著延缓疾病进展，并使小鼠的平均寿命延长~50% 这些老鼠。雷帕霉素还可以延长野生型小鼠的寿命，延缓易患癌症的小鼠的癌症发病， 改善阿尔茨海默氏症模型的神经功能，并防止其他衰老的标志。我们积累了 从NDUFS4分离的脑组织中这种小分子重塑代谢组的重要证据- KO小鼠，包括NAD+水平降低和从糖酵解转变为氨基酸分解代谢。 我的团队最近观察到mTOR和蛋白激酶C(PKC)途径在 雷帕霉素处理NDUFS4-KO小鼠的蛋白质组分析。这一数据揭示了一种未知的 线粒体生理学中mTORC2和PKC信号通路的关系我已经获得了 有证据表明，抑制PKCs延长了这些小鼠的寿命，确立了它在急性髓细胞白血病病理中的作用 线粒体疾病。这项提议将描述这种关系的特征，阐明其机制含义， 并发现新的药物干预措施以防止线粒体疾病的进展 基于我的初步数据的假设驱动的方法。我将阐明钙依赖的作用 线粒体相关内质网膜上的信号转导和单个PKC在疾病中的重要性 通过化学和遗传抑制的表型。总的来说，这些相辅相成的基础科学研究将 更好地了解线粒体生物学，揭示信号通路在线粒体中的作用 疾病，并阐明细胞器间通讯的新机制。这些目标的实现 甚至可能在预防阿尔茨海默氏症、癌症、 和心脏病。

Mitochondrial dysfunction pathologically causes many incurable diseases such as the neurometabolic disease Leigh Syndrome almost certainly resulting in childhood death. It additionally exacerbates most late- onset diseases such as cancer, Alzheimer's, and heart disease. To help fill the unmet medical need for new treatments that prevent the onset of these diseases, the Kaeberlein Group focuses on elucidating novel mechanisms of mitochondrial disease progression and the development of effective pharmacological interventions with specific molecular targets. To do this, we utilize the leading mammalian model of Leigh Syndrome missing the electron transport chain structural protein subunit NDUFS4. These mice exhibit a severe neurodegenerative phenotype and premature death. My group recently discovered the FDA-approved mTOR inhibitor rapamycin can remarkably attenuate disease progression and increase the mean lifespan by ~50% in these mice. Rapamycin also extends lifespan in wild type mice, delays the onset of cancer in cancer-prone mice, improves neurological function in Alzheimer's models, and prevents other hallmarks of aging. We amassed significant evidence that this small molecule remodels the metabolome in brain tissue isolated from NDUFS4- KO mice, including decreased NAD+ levels and a switch from glycolysis to amino acid catabolism. My group recently observed severe deactivation of the mTOR and protein kinase C (PKC) pathways in rapamycin-treated NDUFS4-KO mice by phosphoproteomic analysis. This data revealed an unknown relationship between the mTORC2 and PKC signaling pathways in mitochondrial physiology. I have acquired evidence that inhibition of PKCs extends lifespan in these mice, establishing its role in the pathology of mitochondrial disease. This proposal will characterize this relationship, elucidate its mechanistic implications, and discover new pharmacological interventions to prevent mitochondrial disease progression taking a hypothesis driven approach based on my preliminary data. I will illuminate the role of calcium-dependent signaling in mitochondria-associated ER membranes and probe the importance of individual PKCs in the disease phenotype through chemical and genetic inhibition. Collectively, these complementary basic science studies will provide a better understanding of mitochondrial biology, uncover the role of signaling pathways in mitochondrial disease, and illuminate novel mechanisms of interorganellar communication. The achievement of these aims may even have broad implications in the prevention of diseases of normative aging such as Alzheimer’s, cancer, and heart disease.