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| Home > Publications database > Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways. |
| Home > Publications database > Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways. |
| Journal Article | DKFZ-2025-00890 |
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2025
Springer International Publishing AG
Cham (ZG)
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Please use a persistent id in citations: doi:10.1007/s00018-025-05695-9
Abstract: Balanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.
Keyword(s): Animals (MeSH) ; TOR Serine-Threonine Kinases: metabolism (MeSH) ; TOR Serine-Threonine Kinases: genetics (MeSH) ; Iron: metabolism (MeSH) ; Ferritins: metabolism (MeSH) ; Ferritins: genetics (MeSH) ; NF-E2-Related Factor 2: metabolism (MeSH) ; Homeostasis (MeSH) ; Signal Transduction (MeSH) ; Proto-Oncogene Proteins c-akt: metabolism (MeSH) ; Mice, Knockout (MeSH) ; Muscle, Skeletal: metabolism (MeSH) ; Mice (MeSH) ; Autophagy (MeSH) ; Ferroportin (MeSH) ; Cation Transport Proteins: metabolism (MeSH) ; Cation Transport Proteins: genetics (MeSH) ; Receptors, Transferrin: metabolism (MeSH) ; Basic Helix-Loop-Helix Transcription Factors: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Nuclear Receptor Coactivators: metabolism (MeSH) ; Male (MeSH) ; Autophagy ; Dystrophy ; Glycogen ; Iron-sulfur cluster ; Myoglobin ; Oxidative stress ; TOR Serine-Threonine Kinases ; Iron ; Ferritins ; NF-E2-Related Factor 2 ; Proto-Oncogene Proteins c-akt ; mTOR protein, mouse ; Ferroportin ; Nfe2l2 protein, mouse ; Cation Transport Proteins ; Receptors, Transferrin ; Basic Helix-Loop-Helix Transcription Factors ; Nuclear Receptor Coactivators
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