The goal of this research is to understand how mitochondrial transport, distribution and metabolism are regulated in neurons. Most neurodegenerative diseases involve mitochondrial dysfunction, and many result directly from specific failures of mitochondrial traffic, distribution or metabolism. This is probably because the size and asymmetry of neurons result in a non- uniform distribution of demand for mitochondrial functions such as ATP synthesis. As a result, neurons must extensively redistribute their mitochondria in response to local physiological conditions, both in vivo and in vitro. Mitochondria are transported and redistributed within the axon by several motor proteins that translocate along microtubule and actin tracks, as well as by docking interactions. But how movement, docking and mitochondrial metabolism are regulated and coordinated to deliver the right amount of function to the right location at the right time remains unclear. Our efforts to understand these events are focused on both the specific proteins involved in transport and docking, and on larger-scale processes in the healthy and diseased nervous system. In the first two aims, we will test the hypotheses that mitochondrial distribution is regulated by myosin-based disruptions of protracted movements and by inhibition of MT-based motor activities, and is controlled by signaling kinases. We will use double- stranded RNA inhibition to knock down expression of myosins V, VI and II and kinesin- regulating kinases in isolated Drosophila neurons and quantify the resulting transport phenotypes. We will also use observation of mitochondrial traffic in segmental nerve axons of intact larvae to assess the transport phenotype of myosin mutations. In the third aim, we will use Drosophila models of human mitochondrial diseases to critically assess the hypothesis that the proximal cause of neuropathology in mitochondrial neurodegenerative disease is oxidative damage rather than defects in mitochondrial transport or metabolism. Using quantitative fluorescence microscopy methods, we will determine the relationships among mitochondrial traffic, metabolism and reactive oxygen species production throughout the nervous system and across development in models for Friedriech ataxia, Barth syndrome and other disorders.

Public Health Relevance

Nearly all neurodegenerative diseases are now thought to involve some kind of mitochondrial dysfunction, and many to result directly from specific failures of mitochondrial traffic, distribution, or metabolism. The proposed research seeks to understand the regulation of mitochondrial movements in neurons, and the relationship between those movements and other aspects of mitochondrial function, particularly in animal models of human mitochondrial disease. Our hope is that this knowledge will aid in designing new treatments for these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027073-22
Application #
8259156
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Gwinn, Katrina
Project Start
1990-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
22
Fiscal Year
2012
Total Cost
$319,093
Indirect Cost
$104,718
Name
Purdue University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Hollenbeck, Peter J (2014) Directing traffic and autophagy in axonal transport. Dev Cell 29:505-6
Amiri, Mandana; Hollenbeck, Peter J (2008) Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol 68:1348-61
Verburg, Jessica; Hollenbeck, Peter J (2008) Mitochondrial membrane potential in axons increases with local nerve growth factor or semaphorin signaling. J Neurosci 28:8306-15
Hollenbeck, Peter J; Saxton, William M (2005) The axonal transport of mitochondria. J Cell Sci 118:5411-9
Hollenbeck, Peter J (2005) Mitochondria and neurotransmission: evacuating the synapse. Neuron 47:331-3
Chada, Sonita R; Hollenbeck, Peter J (2004) Nerve growth factor signaling regulates motility and docking of axonal mitochondria. Curr Biol 14:1272-6
Ruthel, Gordon; Hollenbeck, Peter J (2003) Response of mitochondrial traffic to axon determination and differential branch growth. J Neurosci 23:8618-24
Hollenbeck, Peter J; Fekete, D M (2003) Expression of transgenes in primary neurons from chick peripheral and central nervous systems by retroviral infection of early embryos. Methods Cell Biol 71:369-86
Lee, Sun-Kyung; Hollenbeck, Peter J (2003) Organization and translation of mRNA in sympathetic axons. J Cell Sci 116:4467-78
Martinez, Cecilia Y; Hollenbeck, Peter J (2003) Transfection of primary central and peripheral nervous system neurons by electroporation. Methods Cell Biol 71:339-51

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