Indeed, loss of Sarm1 protects sensory neurons and their axons from prolonged exposure to ROS. The survival of these neurons despite the accumulation of ROS indicates that Sarm1 acts downstream of ROS generation. 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. Instead, the axodestructive factor Sarm1 is required for this axon degeneration and cell death. These degenerative events are not blocked by inhibitors of canonical programmed cell death pathways such as apoptosis, necroptosis, and parthanatos. Here, we demonstrate that mitochondrial depolarization triggers axon degeneration and cell death in primary mouse sensory neurons.
Notably, loss of mitochondrial potential precedes cellular demise in several programmed cell destruction pathways, including axons undergoing Wallerian degeneration. 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).
Mitochondrial dysfunction is the underlying cause of many neurological disorders, including peripheral neuropathies.
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