RRC ID 75945
Author Ding C, Wu Y, Dabas H, Hammarlund M.
Title Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria.
Journal Elife
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.
Volume 11
Published 2022-3-14
DOI 10.7554/eLife.73557
PII 73557
PMID 35285800
PMC PMC8920508
MeSH Animals Armadillo Domain Proteins* / metabolism Axons / physiology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism Cytoskeletal Proteins / metabolism Membrane Proteins / metabolism Mitochondria / metabolism p38 Mitogen-Activated Protein Kinases / genetics p38 Mitogen-Activated Protein Kinases / metabolism
C.elegans tm1966 tm2933 tm2807 tm718