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@ARTICLE{ConjardDuplany:300710,
      author       = {A. Conjard-Duplany and A. Osseni and A. Lamboux and S.
                      Mouradian and F. Picard and V. Moncollin and C. Angleraux
                      and T. Dorel-Dubois and H. Puccio and P. Leblanc and B.
                      Galy$^*$ and V. Balter and L. Schaeffer and Y.-G. Gangloff},
      title        = {{M}uscle m{TOR} controls iron homeostasis and
                      ferritinophagy via {NRF}2, {HIF}s and {AKT}/{PKB} signaling
                      pathways.},
      journal      = {Cellular and molecular life sciences},
      volume       = {82},
      number       = {1},
      issn         = {1420-682X},
      address      = {Cham (ZG)},
      publisher    = {Springer International Publishing AG},
      reportid     = {DKFZ-2025-00890},
      pages        = {178},
      year         = {2025},
      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.},
      keywords     = {Animals / TOR Serine-Threonine Kinases: metabolism / TOR
                      Serine-Threonine Kinases: genetics / Iron: metabolism /
                      Ferritins: metabolism / Ferritins: genetics / NF-E2-Related
                      Factor 2: metabolism / Homeostasis / Signal Transduction /
                      Proto-Oncogene Proteins c-akt: metabolism / Mice, Knockout /
                      Muscle, Skeletal: metabolism / Mice / Autophagy /
                      Ferroportin / Cation Transport Proteins: metabolism / Cation
                      Transport Proteins: genetics / Receptors, Transferrin:
                      metabolism / Basic Helix-Loop-Helix Transcription Factors:
                      metabolism / Mice, Inbred C57BL / Nuclear Receptor
                      Coactivators: metabolism / Male / Autophagy (Other) /
                      Dystrophy (Other) / Glycogen (Other) / Iron-sulfur cluster
                      (Other) / Myoglobin (Other) / Oxidative stress (Other) / TOR
                      Serine-Threonine Kinases (NLM Chemicals) / Iron (NLM
                      Chemicals) / Ferritins (NLM Chemicals) / NF-E2-Related
                      Factor 2 (NLM Chemicals) / Proto-Oncogene Proteins c-akt
                      (NLM Chemicals) / mTOR protein, mouse (NLM Chemicals) /
                      Ferroportin (NLM Chemicals) / Nfe2l2 protein, mouse (NLM
                      Chemicals) / Cation Transport Proteins (NLM Chemicals) /
                      Receptors, Transferrin (NLM Chemicals) / Basic
                      Helix-Loop-Helix Transcription Factors (NLM Chemicals) /
                      Nuclear Receptor Coactivators (NLM Chemicals)},
      cin          = {D430},
      ddc          = {610},
      cid          = {I:(DE-He78)D430-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40293459},
      doi          = {10.1007/s00018-025-05695-9},
      url          = {https://inrepo02.dkfz.de/record/300710},
}