ROS regulation of axonal mitochondrial transport

<p>Mitochondria perform critical functions including aerobic ATP production and calcium (Ca2+) homeostasis, but are also a major source of reactive oxygen species (ROS) production. To maintain cellular function and survival in neurons, mitochondria are transported along axons, and accumulate in regions with high demand for their functions. Oxidative stress and abnormal mitochondrial axonal transport are associated with neurodegenerative disorders. However, we know little about the connection between these two. Using primary<em>Drosophila</em> neuronal cell culture and the third instar larval nervous system as in vitro and in vivo models, respectively, we studied mitochondrial transport under oxidative stress conditions. <em>In vitro</em>, hydrogen peroxide (H2O2) diminished the percentage of moving mitochondria, the mitochondrial length and inner membrane potential. <em>In vivo</em>, ROS inhibited specifically mitochondrial axonal transport, primarily due to reduced flux and velocity, but did not affect transport of other organelles. In addition to excess ROS, down-regulation of Nox or Duox expression, which reduces endogenous ROS levels, mitochondrial transport was impaired. To understand the mechanisms underlying these effects, we examined Ca2+ levels and the JNK (c-Jun N-terminal Kinase) pathway, which have been shown to regulate mitochondrial transport and general fast axonal transport, respectively. We found that elevated ROS increased Ca 2+levels, and that the Ca2+ chelator EGTA rescued ROS-induced defects in mitochondrial transport. In addition, activation of the JNK pathway reduced mitochondrial flux and velocities, while JNK knockdown partially rescued ROS-induced defects in the anterograde direction. We conclude that ROS have the capacity to regulate mitochondrial traffic, and that Ca 2+ and JNK signaling play roles in mediating these effects.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biological Science

Year

2016

Author dc:creator

• Liao, Pin-Chao

Contributors dc:contributor

• Peter J. Hollenbeck
• Henry C. Chang
• Jean-Christophe Rochet
• Daniel M. Suter

• Biological sciences
• Axonal transport
• Mitochondrion
• Oxidative stress
• Reactive oxygen species
• Biology
• Cell Biology
• Neuroscience and Neurobiology

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/966

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-2183