PMID- 36793649
OWN - NLM
STAT- MEDLINE
DCOM- 20230217
LR  - 20230217
IS  - 2532-1900 (Electronic)
IS  - 1128-2460 (Print)
IS  - 1128-2460 (Linking)
VI  - 41
IP  - 4
DP  - 2022
TI  - Torin1 restores proliferation rate in Charcot-Marie-Tooth disease type 2A cells 
      harbouring MFN2 (mitofusin 2) mutation.
PG  - 201-206
LID - 10.36185/2532-1900-085 [doi]
AB  - OBJECTIVE: Mitofusin 2 (MFN2) is a mitochondrial outer membrane protein that 
      serves primarily as a mitochondrial fusion protein but has additional functions 
      including the tethering of mitochondrial-endoplasmic reticulum membranes, 
      movement of mitochondria along axons, and control of the quality of mitochondria. 
      Intriguingly, MFN2 has been referred to play a role in regulating cell 
      proliferation in several cell types such that it acts as a tumour suppressor role 
      in some forms of cancer. Previously, we found that fibroblasts derived from a 
      Charcot-Marie-Tooth disease type 2A (CMT2A) patient with a mutation in the GTPase 
      domain of MFN2 exhibit increased proliferation and decreased autophagy. METHODS: 
      Primary fibroblasts from a young patient affected by CMT2A harbouring c.650G > 
      T/p.Cys217Phe mutation in the MFN2 gene were evaluated versus a healthy control 
      to measure the proliferation rate by growth curves analysis and to assess the 
      phosphorylation of protein kinase B (AKT) at Ser473 in response to different 
      doses of torin1, a selective catalytic ATP-competitive mammalian target of 
      rapamycin complex (mTOR) inhibitor, by immunoblot analysis. RESULTS: Herein, we 
      demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) is highly 
      activated in the CMT2A(MFN2) fibroblasts to promote cell growth via the 
      AKT(Ser473) phosphorylation-mediated signalling. We report that torin1 restores 
      CMT2A(MFN2) fibroblasts' growth rate in a dose-dependent manner by decreasing 
      AKT(Ser473) phosphorylation. CONCLUSIONS: Overall, our study provides evidence 
      for mTORC2, as a novel molecular target that lies upstream of AKT to restore the 
      cell proliferation rate in CMT2A fibroblasts.
CI  - (c)2022 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.
FAU - Zanfardino, Paola
AU  - Zanfardino P
AD  - Department of Translational Biomedicine and Neuroscience (DiBraiN), University of 
      Bari "Aldo Moro", Bari, Italy.
FAU - Amati, Alessandro
AU  - Amati A
AD  - Department of Translational Biomedicine and Neuroscience (DiBraiN), University of 
      Bari "Aldo Moro", Bari, Italy.
FAU - Petracca, Easter Anna
AU  - Petracca EA
AD  - Department of Translational Biomedicine and Neuroscience (DiBraiN), University of 
      Bari "Aldo Moro", Bari, Italy.
FAU - Santorelli, Filippo M
AU  - Santorelli FM
AD  - Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS 
      Fondazione Stella Maris, Pisa, Italy.
FAU - Petruzzella, Vittoria
AU  - Petruzzella V
AD  - Department of Translational Biomedicine and Neuroscience (DiBraiN), University of 
      Bari "Aldo Moro", Bari, Italy.
LA  - eng
PT  - Journal Article
DEP - 20221231
PL  - Italy
TA  - Acta Myol
JT  - Acta myologica : myopathies and cardiomyopathies : official journal of the 
      Mediterranean Society of Myology
JID - 9811169
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Membrane Proteins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.1.- (MFN2 protein, human)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - Charcot-Marie-Tooth disease, Type 2A
SB  - IM
MH  - Humans
MH  - *Charcot-Marie-Tooth Disease/genetics
MH  - Proto-Oncogene Proteins c-akt/genetics
MH  - Mutation
MH  - Mitochondrial Proteins/genetics/metabolism
MH  - Membrane Proteins/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics
MH  - Cell Proliferation/genetics
MH  - GTP Phosphohydrolases/genetics
PMC - PMC9896598
OTO - NOTNLM
OT  - AKT
OT  - Charcot-Marie-Tooth type 2A2
OT  - cell proliferation
OT  - mTORC2
OT  - mitofusin2
EDAT- 2023/02/17 06:00
MHDA- 2023/02/18 06:00
PMCR- 2022/12/31
CRDT- 2023/02/16 02:19
PHST- 2022/12/23 00:00 [received]
PHST- 2022/12/30 00:00 [accepted]
PHST- 2023/02/16 02:19 [entrez]
PHST- 2023/02/17 06:00 [pubmed]
PHST- 2023/02/18 06:00 [medline]
PHST- 2022/12/31 00:00 [pmc-release]
AID - 10.36185/2532-1900-085 [doi]
PST - epublish
SO  - Acta Myol. 2022 Dec 31;41(4):201-206. doi: 10.36185/2532-1900-085. eCollection 
      2022.