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.
Neurons are among the most long-lived cell types in our bodies, as they are generally never replaced and must a maintain function for our entire lifetime. One vital aspect of maintaining neuronal health is the preservation of a healthy pool of the energy-producing organelle within the cell, the mitochondria, as multiple neurodegenerative diseases are caused by defects in mitochondrial function. The work in this proposal will study a newly discovered way in which neurons break down their damaged mitochondria through outsourcing this breakdown process to their cellular neighbors known as glial cells.
