This proposal describes a pre-doctoral research-training plan and research strategy designed to support the principal investigator's development into an independent neuroscientist. The goal of this proposal is to understand how defective mitochondrial movement and function contribute to neurodegenerative diseases. Nearly all neurodegenerative diseases involve mitochondrial distribution defects and respiratory dysfunction. Neurons are susceptible to mitochondrial dysfunction because they have high ATP demands and are polarized cells. In neurons, mitochondria are moved and redistributed within the axon towards either the synaptic terminal (anterograde) or to the cell body (retrograde) by an outer mitochondrial membrane protein, Miro. Current data suggest that anterograde mitochondrial movement supplies ATP for synaptic release, and retrograde mitochondrial movement is important for organelle clearance. However, how the direction of mitochondrial movement is determined and the relationship between movement and mitochondrial metabolism in neurons is unclear. To better understand these events and how they relate to neurodegenerative diseases, we will disrupt Miro- mediated mitochondrial movement and determine the effect on mitochondrial function, mitochondrial distribution in neurons and neurodegeneration. Using Miro1 KO mice generated by the applicant and quantitative fluorescence microscopy methods, we will determine mitochondrial anterograde and retrograde movements in axons. We will also assess mitochondrial homeostasis by measuring mitochondrial membrane potential and mitochondrial genome loss. Finally, we will evaluate the neurological and metabolic consequence of disrupting mitochondrial movement throughout development in whole animals by neurological exams, neural sectioning and metabolic phenotyping methods.
Understanding the molecular regulation of mitochondrial movements in neurons and the relationship between those movements and mitochondrial function is important for developing new therapeutic interventions to treat neurodegenerative disease caused by mitochondrial dysfunction. In addition to the proposed research, a customized training plan is outlined under the mentorship of experts in neurodegenerative diseases and mitochondrial biology.
A number of important questions regarding the pathogenesis of neurodegenerative diseases remain unanswered. First, does disruption of axonal mitochondrial movement deteriorate neuron function? Second, is mitochondrial movement essential for mitochondrial respiratory function? Third, does Miro dysfunction alter mitochondrial distribution and lead neurodegeneration in mammals? If successful, these studies will lead to a better understanding of neurodegeneration related to mitochondrial dysfunction and possibly offer insight towards therapeutic interventions. Therefore, we feel that this proposal has a strong possibility of moving the field forward.
|Nguyen, Tammy T; Oh, Sang S; Weaver, David et al. (2014) Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A 111:E3631-40|