TY  - JOUR
AU  - Conjard-Duplany, Agnès
AU  - Osseni, Alexis
AU  - Lamboux, Aline
AU  - Mouradian, Sandrine
AU  - Picard, Flavien
AU  - Moncollin, Vincent
AU  - Angleraux, Céline
AU  - Dorel-Dubois, Tiphaine
AU  - Puccio, Hélène
AU  - Leblanc, Pascal
AU  - Galy, Bruno
AU  - Balter, Vincent
AU  - Schaeffer, Laurent
AU  - Gangloff, Yann-Gaël
TI  - Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways.
JO  - Cellular and molecular life sciences
VL  - 82
IS  - 1
SN  - 1420-682X
CY  - Cham (ZG)
PB  - Springer International Publishing AG
M1  - DKFZ-2025-00890
SP  - 178
PY  - 2025
AB  - 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.
KW  - Animals
KW  - TOR Serine-Threonine Kinases: metabolism
KW  - TOR Serine-Threonine Kinases: genetics
KW  - Iron: metabolism
KW  - Ferritins: metabolism
KW  - Ferritins: genetics
KW  - NF-E2-Related Factor 2: metabolism
KW  - Homeostasis
KW  - Signal Transduction
KW  - Proto-Oncogene Proteins c-akt: metabolism
KW  - Mice, Knockout
KW  - Muscle, Skeletal: metabolism
KW  - Mice
KW  - Autophagy
KW  - Ferroportin
KW  - Cation Transport Proteins: metabolism
KW  - Cation Transport Proteins: genetics
KW  - Receptors, Transferrin: metabolism
KW  - Basic Helix-Loop-Helix Transcription Factors: metabolism
KW  - Mice, Inbred C57BL
KW  - Nuclear Receptor Coactivators: metabolism
KW  - Male
KW  - Autophagy (Other)
KW  - Dystrophy (Other)
KW  - Glycogen (Other)
KW  - Iron-sulfur cluster (Other)
KW  - Myoglobin (Other)
KW  - Oxidative stress (Other)
KW  - TOR Serine-Threonine Kinases (NLM Chemicals)
KW  - Iron (NLM Chemicals)
KW  - Ferritins (NLM Chemicals)
KW  - NF-E2-Related Factor 2 (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-akt (NLM Chemicals)
KW  - mTOR protein, mouse (NLM Chemicals)
KW  - Ferroportin (NLM Chemicals)
KW  - Nfe2l2 protein, mouse (NLM Chemicals)
KW  - Cation Transport Proteins (NLM Chemicals)
KW  - Receptors, Transferrin (NLM Chemicals)
KW  - Basic Helix-Loop-Helix Transcription Factors (NLM Chemicals)
KW  - Nuclear Receptor Coactivators (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40293459
DO  - DOI:10.1007/s00018-025-05695-9
UR  - https://inrepo02.dkfz.de/record/300710
ER  -