Membrane-anchored Miro GTPases and their adaptor proteins attach mitochondria to cytoskeletal motors that distribute the organelle throughout the cell. This process is particularly important in neurons, where mitochondria are moved long distances from the cell body to the synapse and back again. Aberrant mitochondrial movement and distribution is observed in a large number of human neurodegenerative disorders including Spastic paraplegias, Alzheimer's, Huntington's and Parkinson's diseases. A popular model proposes that energy (ATP) deprivation and changes in calcium buffering caused by mitochondrial distribution defects causes the neuronal degeneration associated with these diseases. However, whether mitochondrial motility defects are a primary cause or a secondary consequence of disease progression in these cases is not clear. The research proposed in this application will directly test this model. Using a conditional (floxed) allele, we generated two different Miro1 mutant mouse models. The first is a Miro1 neuron-specific KO that allows mice to survive postnatally, but causes a progressive neuropathy characterized by tremors, hind limb stiffness, kyphosis (spinal curvature) movement defects and death several weeks after birth. These phenotypes are hallmarks of neurodegenerative disorders. The second is a whole animal knockout (KO), which completes embryogenesis but fails to breathe and dies at birth. Preliminary studies indicate that defects in a specific neuronal circuit are responsible for this neonatal breathing defect. Using these mice as well as tissues and primary cell cultures from these animals, we will determine the effects of Miro1 loss on mitochondrial distribution and function. We will also determine whether/how any mitochondrial defects lead to neuronal degeneration and death. These studies will provide the first physiological analysis of Miro1 function and specific mitochondrial movement defects in mammals. Because our studies are based on mouse models with demonstrated neurological dysfunction, what we learn will advance understanding of the role of mitochondrial movement in the development and maintenance of neuronal health.
This project tests a current model for the role of mitochondrial movement and distribution in neuron maintenance and neurodegeneration in mammals. The findings will advance understanding of the pathology of neurodegeneration observed in human motor neuron diseases such as spastic paraplegia.
