%0 Journal Article
%A Conjard-Duplany, Agnès
%A Osseni, Alexis
%A Lamboux, Aline
%A Mouradian, Sandrine
%A Picard, Flavien
%A Moncollin, Vincent
%A Angleraux, Céline
%A Dorel-Dubois, Tiphaine
%A Puccio, Hélène
%A Leblanc, Pascal
%A Galy, Bruno
%A Balter, Vincent
%A Schaeffer, Laurent
%A Gangloff, Yann-Gaël
%T Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways.
%J Cellular and molecular life sciences
%V 82
%N 1
%@ 1420-682X
%C Cham (ZG)
%I Springer International Publishing AG
%M DKFZ-2025-00890
%P 178
%D 2025
%X 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.
%K Animals
%K TOR Serine-Threonine Kinases: metabolism
%K TOR Serine-Threonine Kinases: genetics
%K Iron: metabolism
%K Ferritins: metabolism
%K Ferritins: genetics
%K NF-E2-Related Factor 2: metabolism
%K Homeostasis
%K Signal Transduction
%K Proto-Oncogene Proteins c-akt: metabolism
%K Mice, Knockout
%K Muscle, Skeletal: metabolism
%K Mice
%K Autophagy
%K Ferroportin
%K Cation Transport Proteins: metabolism
%K Cation Transport Proteins: genetics
%K Receptors, Transferrin: metabolism
%K Basic Helix-Loop-Helix Transcription Factors: metabolism
%K Mice, Inbred C57BL
%K Nuclear Receptor Coactivators: metabolism
%K Male
%K Autophagy (Other)
%K Dystrophy (Other)
%K Glycogen (Other)
%K Iron-sulfur cluster (Other)
%K Myoglobin (Other)
%K Oxidative stress (Other)
%K TOR Serine-Threonine Kinases (NLM Chemicals)
%K Iron (NLM Chemicals)
%K Ferritins (NLM Chemicals)
%K NF-E2-Related Factor 2 (NLM Chemicals)
%K Proto-Oncogene Proteins c-akt (NLM Chemicals)
%K mTOR protein, mouse (NLM Chemicals)
%K Ferroportin (NLM Chemicals)
%K Nfe2l2 protein, mouse (NLM Chemicals)
%K Cation Transport Proteins (NLM Chemicals)
%K Receptors, Transferrin (NLM Chemicals)
%K Basic Helix-Loop-Helix Transcription Factors (NLM Chemicals)
%K Nuclear Receptor Coactivators (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40293459
%R 10.1007/s00018-025-05695-9
%U https://inrepo02.dkfz.de/record/300710