Supplying axons, dendrites, and synapses with mitochondria is vital for sustaining neuronal excitability and synaptic transmission. In contrast to most other cells, mitochondrial transport is critical for neuronal survival, as impaired transport causes the same pathology as impaired mitochondrial function. A combination of the large distance between soma and synapses, the complexity of neuronal branches, the need to relocate mitochondria in response to changes in neuronal activity, coupled with the need of mitochondria to eventually return to the cell body requires a transport system that is sensitive to pathways communicating the """"""""energetic state of the neuron"""""""" and the """"""""state of the mitochondrion"""""""". However, we know little about the link between mitochondrial transport and mechanisms that maintain mitochondrial function in axons. A better understanding is urgently needed because even slight impairments of mitochondrial function and/or distribution can cause or intensify neuropathy, neurodegeneration, and/or paraplegia. The evolutionarily conserved mitochondrial GTPase Miro contains two Ca2+ binding domains sandwiched between Rho- and Rab-like GTPase (G) domains. Our genetic analysis shows that mutations in Miro have pleiotropic effects on the biology of mitochondria in axons. We hypothesize that Miro is a central integration node for multimodal signals that controls distinct mechanisms including mitochondrial transport, mitochondrial fusion &fission and autophagy. To test this further, we are taking advantage of the model system Drosophila to elucidate the multiple roles of Miro in neurons by genetically manipulating Miro and its interacting proteins.
Aim 1 will characterize how Miro's G1 domain promotes the use of kinesin for anterograde transport and the use of dynein for retrograde transport in axons.
Aim 2 will characterize the Ca2+-sensitive role of Miro for mitochondrial function in axons.
Aim 3 will characterize the role of Miro for mitochondrial fusion &fission and/or autophagy. The project is expected to reveal critical insights into molecular signaling mechanisms that ensure mitochondrial function in axons. Uncovering these pathways will expand our understanding of logistical mechanisms that are critical for the long-term survival of neurons.

Public Health Relevance

The project is expected to reveal critical insights into molecular signaling mechanisms that control mitochondrial transport, fusion &fission, and health in axons. Uncovering these pathways will expand our understanding of logistical mechanisms that are critical for the long-term survival of neurons and accelerate the development of new concepts for detecting, treating, and/or preventing disorders that are caused or aggravated by mitochondrial malfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052664-08
Application #
8653841
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Stewart, Randall R
Project Start
2007-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arizona
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Babic, Milos; Russo, Gary J; Wellington, Andrea J et al. (2015) Miro's N-terminal GTPase domain is required for transport of mitochondria into axons and dendrites. J Neurosci 35:5754-71
Tsai, Pei-I; Course, Meredith M; Lovas, Jonathan R et al. (2014) PINK1-mediated phosphorylation of Miro inhibits synaptic growth and protects dopaminergic neurons in Drosophila. Sci Rep 4:6962
Zinsmaier, Konrad E (2010) Cysteine-string protein's neuroprotective role. J Neurogenet 24:120-32
Russo, Gary J; Louie, Kathryn; Wellington, Andrea et al. (2009) Drosophila Miro is required for both anterograde and retrograde axonal mitochondrial transport. J Neurosci 29:5443-55
Zarnescu, Daniela C; Zinsmaier, Konrad E (2009) Ferrying wingless across the synaptic cleft. Cell 139:229-31
Louie, Kathryn; Russo, Gary J; Salkoff, David B et al. (2008) Effects of imaging conditions on mitochondrial transport and length in larval motor axons of Drosophila. Comp Biochem Physiol A Mol Integr Physiol 151:159-72