Home > Publications database > Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways. > print

001     300710
005     20250504020351.0
024 7 _ |a 10.1007/s00018-025-05695-9
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024 7 _ |a 1420-682X
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024 7 _ |a 0014-4754
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024 7 _ |a 1420-9071
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037 _ _ |a DKFZ-2025-00890
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Conjard-Duplany, Agnès
|0 0000-0002-3485-1597
|b 0
245 _ _ |a Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways.
260 _ _ |a Cham (ZG)
|c 2025
|b Springer International Publishing AG
336 7 _ |a article
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336 7 _ |a Journal Article
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520 _ _ |a 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.
536 _ _ |a 314 - Immunologie und Krebs (POF4-314)
|0 G:(DE-HGF)POF4-314
|c POF4-314
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a Autophagy
|2 Other
650 _ 7 |a Dystrophy
|2 Other
650 _ 7 |a Glycogen
|2 Other
650 _ 7 |a Iron-sulfur cluster
|2 Other
650 _ 7 |a Myoglobin
|2 Other
650 _ 7 |a Oxidative stress
|2 Other
650 _ 7 |a TOR Serine-Threonine Kinases
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a Iron
|0 E1UOL152H7
|2 NLM Chemicals
650 _ 7 |a Ferritins
|0 9007-73-2
|2 NLM Chemicals
650 _ 7 |a NF-E2-Related Factor 2
|2 NLM Chemicals
650 _ 7 |a Proto-Oncogene Proteins c-akt
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a mTOR protein, mouse
|0 EC 2.7.1.1
|2 NLM Chemicals
650 _ 7 |a Ferroportin
|2 NLM Chemicals
650 _ 7 |a Nfe2l2 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Cation Transport Proteins
|2 NLM Chemicals
650 _ 7 |a Receptors, Transferrin
|2 NLM Chemicals
650 _ 7 |a Basic Helix-Loop-Helix Transcription Factors
|2 NLM Chemicals
650 _ 7 |a Nuclear Receptor Coactivators
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a TOR Serine-Threonine Kinases: metabolism
|2 MeSH
650 _ 2 |a TOR Serine-Threonine Kinases: genetics
|2 MeSH
650 _ 2 |a Iron: metabolism
|2 MeSH
650 _ 2 |a Ferritins: metabolism
|2 MeSH
650 _ 2 |a Ferritins: genetics
|2 MeSH
650 _ 2 |a NF-E2-Related Factor 2: metabolism
|2 MeSH
650 _ 2 |a Homeostasis
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Proto-Oncogene Proteins c-akt: metabolism
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Muscle, Skeletal: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Autophagy
|2 MeSH
650 _ 2 |a Ferroportin
|2 MeSH
650 _ 2 |a Cation Transport Proteins: metabolism
|2 MeSH
650 _ 2 |a Cation Transport Proteins: genetics
|2 MeSH
650 _ 2 |a Receptors, Transferrin: metabolism
|2 MeSH
650 _ 2 |a Basic Helix-Loop-Helix Transcription Factors: metabolism
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Nuclear Receptor Coactivators: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
700 1 _ |a Osseni, Alexis
|0 0000-0003-3435-5785
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700 1 _ |a Lamboux, Aline
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700 1 _ |a Mouradian, Sandrine
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700 1 _ |a Picard, Flavien
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700 1 _ |a Moncollin, Vincent
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700 1 _ |a Angleraux, Céline
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700 1 _ |a Dorel-Dubois, Tiphaine
|b 7
700 1 _ |a Puccio, Hélène
|0 0000-0003-4711-2248
|b 8
700 1 _ |a Leblanc, Pascal
|0 0000-0003-3214-5880
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700 1 _ |a Galy, Bruno
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700 1 _ |a Balter, Vincent
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700 1 _ |a Schaeffer, Laurent
|0 0000-0001-6600-503X
|b 12
700 1 _ |a Gangloff, Yann-Gaël
|0 0000-0001-9031-1184
|b 13
773 _ _ |a 10.1007/s00018-025-05695-9
|g Vol. 82, no. 1, p. 178
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|y 2025
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