Journal article
Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons
The Journal of neuroscience, Vol.34(28), pp.9338-9350
07/09/2014
DOI: 10.1523/JNEUROSCI.0877-14.2014
PMCID: PMC4087211
PMID: 25009267
Abstract
Mitochondrial dysfunction is the underlying cause of many neurological disorders, including peripheral neuropathies. Mitochondria rely on a proton gradient to generate ATP and interfering with electron transport chain function can lead to the deleterious accumulation of reactive oxygen species (ROS). Notably, loss of mitochondrial potential precedes cellular demise in several programmed cell destruction pathways, including axons undergoing Wallerian degeneration. Here, we demonstrate that mitochondrial depolarization triggers axon degeneration and cell death in primary mouse sensory neurons. These degenerative events are not blocked by inhibitors of canonical programmed cell death pathways such as apoptosis, necroptosis, and parthanatos. Instead, the axodestructive factor Sarm1 is required for this axon degeneration and cell death. In the absence of Sarm1, the mitochondrial poison CCCP still induces depolarization of mitochondria, ATP depletion, calcium influx, and the accumulation of ROS, yet cell death and axon degeneration are blocked. The survival of these neurons despite the accumulation of ROS indicates that Sarm1 acts downstream of ROS generation. Indeed, loss of Sarm1 protects sensory neurons and their axons from prolonged exposure to ROS. Therefore, Sarm1 functions downstream of ROS to induce neuronal cell death and axon degeneration during oxidative stress. These findings highlight the central role for Sarm1 in a novel form of programmed cell destruction that we term sarmoptosis.
Details
- Title: Subtitle
- Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons
- Creators
- Daniel W Summers - Department of Genetics, Department of Developmental Biology, andAaron DiAntonio - Department of Developmental Biology, and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110 jmilbrandt@wustl.edu diantonio@wustl.eduJeffrey Milbrandt - Department of Genetics, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110 jmilbrandt@wustl.edu diantonio@wustl.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.34(28), pp.9338-9350
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.0877-14.2014
- PMID
- 25009267
- PMCID
- PMC4087211
- ISSN
- 1529-2401
- eISSN
- 1529-2401
- Grant note
- R01NS078007 / NINDS NIH HHS R01NS065053 / NINDS NIH HHS R01 DA020812 / NIDA NIH HHS R01 AG013730 / NIA NIH HHS 2T32CA9547 / NCI NIH HHS R01DA020812 / NIDA NIH HHS R01 NS078007 / NINDS NIH HHS R01AG013730 / NIA NIH HHS T32 CA009547 / NCI NIH HHS R01 NS065053 / NINDS NIH HHS
- Language
- English
- Date published
- 07/09/2014
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9983991965002771
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