Mechanistic investigation of in vivo pathways of neuronal mitochondrial degradation

神经元是身体中最需要能量的细胞类型之一，因此，严重依赖于 线粒体的输出来为其基本功能提供燃料。正因为如此， 其功能障碍与神经退行性疾病有关，与线粒体功能有关。的 对神经元健康和存活特别重要的是降解线粒体的过程。尽管如此 林克说，人们对介导神经元中线粒体分解的细胞生物学途径知之甚少 在神经组织中的自然生理环境中。该提案的总体目标是获得 进一步了解神经元用来分解线粒体的各种途径。 在神经组织中，神经元从一种称为神经胶质细胞的特殊细胞类型中获得支持。它最近 已经发现，共济失调相关基因Vps13D的敲低导致了对一种免疫抑制剂的强烈抑制。 神经元通过线粒体自噬途径分解线粒体的能力。针对这一强劲的 抑制，神经元适应性地诱导线粒体分解的替代手段，涉及 受损的线粒体转移到支持性神经胶质细胞，以最终降解。的发现 这一新的线粒体降解途径，该建议的指导阶段将使用强大的 与Vps13D缺失相关的表型，以指导研究非细胞自主性的工具的开发 体内神经元线粒体降解。这项工作还将揭示导致 这种跨细胞神经元对神经胶质线粒体破坏的诱导。 在本提案的独立阶段，目标是使用这些新开发的工具， 线粒体是如何从神经元中释放出来的利用强大的基因工具 在果蝇研究中可用，这个目标将测试候选分子与介导细胞间的历史， 线粒体运输其他类型的细胞，以确定它们是否参与神经元到神经胶质细胞 线粒体转移 最后，本提案在独立阶段的目标是确定 新发现的，线粒体降解的替代形式变得适应性更普遍， 随着自噬水平的降低，衰老过程中。然后，这个目标将测试细胞和功能 在老年人的易感人群中， 神经元 在完成本申请书所建议的研究后，申请人将可 独特的利基为一个独立的研究生涯，专注于跨细胞线粒体的细胞生物学 神经元的退化

Neurons are among the most energetically-demanding cell types in the body, and as such, heavily rely on the output of mitochondria to fuel their basic functionality. Because of this, a disproportionate number of genes whose dysfunction is associated with neurodegenerative disease are related to mitochondrial function. Of particular importance to neuronal health and survival is the process of degrading mitochondria. Despite this link, little is known about the cell biological pathways that mediate the breakdown of mitochondria in neurons within their native, physiological environment in nervous tissue. The overall goal of this proposal is to gain a further understanding of the various pathways neurons utilize to break down their mitochondria. Within nervous tissue, neurons get support from a specialized cell type known as glial cells. It has recently been discovered that knock down of the ataxia-associated gene Vps13D leads to the strong inhibition of a neuron’s ability to break down their mitochondria via a pathway known as mitophagy. In response to this robust inhibition, neurons adaptively induce an alternative means of mitochondrial breakdown that involves the transfer of damaged mitochondria to supportive glial cells for their ultimate degradation. With the discovery of this new pathway of mitochondrial degradation, the mentored phase of this proposal will use the robust phenotype associated with loss of Vps13D to guide the development of tools for studying non-cell autonomous mitochondrial degradation in neurons in vivo. This work will also uncover the conditions that lead to the induction of this transcellular neuron to glia mitochondrial breakdown. In the independent phase of this proposal, the goal will be to use these newly developed tools to gain a mechanistic understanding of how mitochondria are released from neurons. Using the powerful genetic tools available in fruit fly research, this Aim will test out candidate molecules with a history of mediating intercellular mitochondrial trafficking in other cell types to determine whether they participate in neuron to glial mitochondrial transfer. Finally, the goal of this proposal in the independent phase will be to determine if this newly discovered, alternative form of mitochondrial degradation become adaptively more prevalent during the course of aging as levels of autophagy decrease. Then, this Aim will test the cellular and functional consequences of disrupting neuron-to-glial transfer of mitochondrial in this susceptible population of aged neurons. With the completion of the research proposed in this application, the applicant will have carved out a distinctive niche for an independent research career focusing on the cell biology of transcellular mitochondrial degradation in neurons.