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J Neurosci. 2014 Jul 9;34(28):9338-50. doi: 10.1523/JNEUROSCI.0877-14.2014.

Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons.

Author information

1
Department of Genetics, Department of Developmental Biology, and.
2
Department of Developmental Biology, and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110 jmilbrandt@wustl.edu diantonio@wustl.edu.
3
Department of Genetics, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110 jmilbrandt@wustl.edu diantonio@wustl.edu.

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.

KEYWORDS:

Sarm1; axon; cell death; degeneration; mitochondria; reactive oxygen species

PMID:
25009267
PMCID:
PMC4087211
DOI:
10.1523/JNEUROSCI.0877-14.2014
[Indexed for MEDLINE]
Free PMC Article

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