Reference - Detail
| RRC ID | 88081 |
|---|---|
| Author | Ryan KC, Laboy JT, Ashraf R, Ashkavand Z, Jayasinghe I, Norman KR. |
| Title | Presenilin mutations disrupt iron homeostasis to promote ferroptosis mediated neurodegeneration in Caenorhabditis elegans. |
| Journal | Redox Biol |
| Abstract |
Iron is a vital trace element involved in numerous physiological processes, but it becomes toxic when present in excess. Disruption of iron balance in the brain has been linked to the development of neurodegenerative diseases such as Alzheimer's disease (AD), though the underlying mechanisms remain poorly understood. Familial forms of AD are primarily caused by mutations in presenilin, which are known to disturb cellular calcium homeostasis. However, the role of iron in presenilin-related neurodegeneration has not been fully explored. Using C. elegans as a model organism, we investigated the function of SEL-12, the worm ortholog of presenilin, and found that loss of SEL-12 leads to elevated iron levels and increased expression of FTN-2/ferritin, an iron-sequestering protein. Notably, reducing mitochondrial calcium in sel-12 mutants prevented this iron accumulation, indicating that elevated mitochondrial calcium drives increased cellular iron levels. This iron overload depends on mitochondrial superoxide production, which occurs alongside heightened mitochondrial calcium, suggesting that oxidative stress contributes to iron dysregulation. The resulting iron imbalance causes mitochondrial and lysosomal dysfunction, ultimately impairing neuronal and behavioral function. Supporting the involvement of iron, sel-12 mutants exhibit elevated lipid peroxidation, and inhibition of ferroptosis restores neuronal function. Together, these findings reveal a novel role for presenilin in regulating iron homeostasis and identify a mechanism linking calcium signaling disruption to iron dyshomeostasis and neurodegeneration. |
| Volume | 88 |
| Pages | 103910 |
| Published | 2025-12-1 |
| DOI | 10.1016/j.redox.2025.103910 |
| PII | S2213-2317(25)00423-9 |
| PMID | 41197184 |
| PMC | PMC12639444 |
| MeSH | Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Calcium / metabolism Disease Models, Animal Ferroptosis* / genetics Homeostasis Iron* / metabolism Mitochondria / metabolism Mutation* Neurodegenerative Diseases* / genetics Neurodegenerative Diseases* / metabolism Neurodegenerative Diseases* / pathology Oxidative Stress Presenilins* / genetics Presenilins* / metabolism |
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| The most frequently cited source | News |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm6026 |