Role of phospholipids in regulating neurotoxin induced mitochondrial autophagy

描述（由申请人提供）：失调的自噬与几种人类神经退行性疾病及其模型有关。大自噬是细胞质成分被吞噬到称为自噬体的细胞器中的一个受调节的过程，自噬体将货物运送到溶酶体进行降解。自噬隔离需要自噬机制的组成部分与自噬体前膜结合。基础自噬是维持神经元线粒体稳态的关键，无论是受损还是过度的线粒体！转换可能导致神经退行性变。然而，调控受损细胞器（如线粒体）选择性靶向的机制尚不清楚。我们最近的研究表明，替代脂质信号参与了线粒体的信号传递！这些信号不同于通常研究的调节非选择性饥饿诱导的自噬的脂质信号。我们假设线粒体的氧化和暴露！内膜磷脂cardlolipln （CL）通过与自噬机制的相互作用触发线粒体自噬。跨学科的方法，包括质谱、高效薄层色谱、脂质包被纳米颗粒、活细胞成像和突变分析，将通过两个特定的目标来验证这一假设，重点关注CL在触发有丝分裂中的作用以及与自噬机制相互作用的机制。申请人为具有分子神经药理学研究经验的博士后。为了进行拟议的研究，他将在自噬细胞生物学和帕金森病机制、氧化脂质组学和纳米技术、计算生物学和专业生物成像技术等多学科专家的指导下进行培训。定期召开由申请人、其跨学科指导团队和外部顾问参加的会议，以确保有效整合分子细胞生物学、生物化学和神经退行性因素。为期两年的研究培训计划将使申请人获得职业发展技能，成为神经退行性疾病研究的独立研究者。总结。除了为细胞提供能量需求外，线粒体还积极调节神经元的生存/死亡决定。线粒体!这些改变与神经退行性和

DESCRIPTION (provided by applicant): Dysregulated autophagy has been implicated in several human neurodegenerative diseases and their models. Macroautophagy is a regulated process for engulfment of cytoplasmic constituents into organelles termed autophagosomes, which deliver the cargo to lysosomes for degradation. Autophagic sequestration requires conjugation of components of the autophagy machinery to the pre-autophagosome membrane.Basal autophagy is critical for maintaining mitochondria) homeostasis in neurons, and either impaired or excessive mitochondria! turnover may contribute to neurodegeneration. However, mechanisms that regulate selective targeting of damaged organelles such as mitochondria are unknown. Our recent study indicates that alternative lipid signals are involved in signaling mitochondria! Autophagy during parkinsonian injury, and these signals are distinct from the commonly studied lipid signals that regulate nonselective starvation-induced autophagy. We hypothesize that oxidation and exposure of the mitochondria! inner membrane phospholipid cardlolipln (CL) triggers mitophagy through interactions with the autophagy machinery. Interdisciplinary approaches including mass spectrometry, high performance thin layer chromatography, lipid coated nanoparticles, live cell imaging, and mutational analysis will be employed to test this hypothesis through two specific aims that focus on the role of CL in triggering mitophagy and the mechanism of interaction with the autophagy machinery. The applicant is a postdoctoral fellow with experience in molecular neuropharmacology. To conduct the proposed studies, he will train under the multidisciplinary mentorship of experts in autophagic cell biology and Parkinson's disease mechanisms, oxidative lipidomics and nanotechnology, computational biology and specialized biologic imaging techniques. Regular meetings involving the applicant, his interdisciplinary mentoring team, and external advisors will be held to ensure effective integration of molecular cell biologic, biochemical and neurodegenerative considerations. The two-year research training plan will enable the applicant to derive career developmental skills to become an independent investigator in neurodegeneration research. Lay Summary. In addition to powering cellular energy needs, mitochondria actively regulate neuronal survival/death decisions. Mitochondria! alterations are implicated in neurodegenerative and psychiatric diseases and in aging. As autophagy is a key factor in mitochondria! quality control, scientific innovations from the proposed research can benefit the larger community by unveiling therapeutically relevant mechanisms in Parkinson's and other age-related neurodegenerative processes.