Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria

Abstract

Mitochondrial defects are tightly linked to axon degeneration, yet the underlying cellular mechanisms remain poorly understood. In Caenorhabditis elegans, PVQ axons that lack mitochondria degenerate spontaneously with age. Using an unbiased genetic screen, we found that cell-specific activation of CaMKII/UNC-43 suppresses axon degeneration due to loss of mitochondria. Unexpectedly, CaMKII/UNC-43 activates the conserved Sarm1/TIR-1-ASK1/NSY-1-p38 MAPK pathway and eventually the transcription factor CEBP-1 to protect against degeneration. In addition, we show that disrupting a trafficking complex composed of calsyntenin/CASY-1, Mint/LIN-10, and kinesin suppresses axon degeneration. Further analysis indicates that disruption of this trafficking complex activates the CaMKII-Sarm1-MAPK pathway through L-type voltage-gated calcium channels. Our findings identify CaMKII as a pivot point between mitochondrial defects and axon degeneration, describe how it is regulated, and uncover a surprising neuroprotective role for the Sarm1-p38 MAPK pathway in this context.

Oral Administration of Glutathione Trisulfide Increases Reactive Sulfur Levels in Dorsal Root Ganglion and Ameliorates Paclitaxel-Induced Peripheral Neuropathy in Mice

“…Our results in primary DRG neurons suggest that GSSSG prevents not only mitochondria fragmentation (or fission) induced by paclitaxel, but also loss of mitochondria in neural axons. As reported previously, redox balance and glutathione oxidation in neural axons partly regulate mitochondrial transportation from cell body to axon [ 40 ], and loss of axonal mitochondria results in axonal degeneration [ 41 ] and neuropathy [ 42 ]. Our observations support that GSSSG attenuates PIPN via protecting mitochondria by regulating redox balance in peripheral neurons.…”

Balancing p38 MAPK Signaling with Proteostasis Mechanisms Supports Tissue Integrity during Aging inC. elegans

“…Intriguingly, this rescue is specific to PMK-3 signaling and not PMK-1 signaling (Ding et al 2022). In the current study, we identified pmk-1-dependent signaling for key gene expression programs to support sensory neuronal integrity during aging in the absence of a stressor.…”

“…Neurodegeneration as a result of expressing mutant TDP-43 or FUS is driven by an innate immune response dependent on PMK-1 signaling (Veriepe et al 2015). In contrast, loss of mitochondria resulting in neurodegeneration is alleviated by activating CaMKII (UNC-43) signaling leading to PMK-3 activation and ultimately CEBP (Ding et al 2022). Intriguingly, this rescue is specific to PMK-3 signaling and not PMK-1 signaling (Ding et al 2022).…”

“…In contrast, loss of mitochondria resulting in neurodegeneration is alleviated by activating CaMKII (UNC-43) signaling leading to PMK-3 activation and ultimately CEBP (Ding et al 2022). Intriguingly, this rescue is specific to PMK-3 signaling and not PMK-1 signaling (Ding et al 2022). In the current study, we identified pmk-1- dependent signaling for key gene expression programs to support sensory neuronal integrity during aging in the absence of a stressor.…”

Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging

“…In day 1 adults, genes regulated by the transcription factor CEBP-1 were upregulated. In C. elegans , CEBP-1 has been shown to activate a gene expression program that protects axons from degeneration [ 56 ]. Genes regulated by NHR-6, a transcription factor expressed in chemosensory neurons found to be important for functional plasticity [ 57 ], were enriched in day 6 adults.…”