SUMMARY:
MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.
TITLE:
Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts
DESCRIPTION:
Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on…
CONTENT:
Hum Mol Genet. 2022 Aug 22:ddac201. doi: 10.1093/hmg/ddac201. Online ahead of print.
ABSTRACT
Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on the mitochondrial altered phenotypes in patient-derived fibroblasts harboring MFN2 mutations and in animal models have been reported. We addressed some of these issues by focusing on mitochondria behavior during autophagy and mitophagy in fibroblasts derived from a CMT2AMFN2 patient with an MFN2650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity, and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. We found that MFN2 mutated fibroblasts showed impairment of mitochondrial morphology, bioenergetics capacity, and impairment of the early stages of autophagy, but not mitophagy. Unexpectedly, transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. We consistently found the activation of mTORC2/AKT signaling and accelerated proliferation in the CMT2AMFN2 fibroblasts. In conclusion, our evidence indicates that MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.
PMID:35994048 | DOI:10.1093/hmg/ddac201
SOURCE:
Human molecular genetics
TAGS:
Mfn2
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-08-22T14:58:30Z
DATE – DOI: 2022-08-22T14:58:30Z
DATE – PUBMED: 2022 Aug 22
DATE OUTPUT MATCHED: True
DATE – ADDED:
Mon, 22 Aug 2022 06:00:00 -0400
DATE – RETRIEVED:
08/22/22 12:59PM
2022-08-22T12:59:34-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:35994048,doi:10.1093/hmg/ddac201
PUBMED ID:
pubmed:35994048
DOI:
10.1093/hmg/ddac201
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35994048/
LINK – DOI:
https://doi.org/10.1093/hmg/ddac201
LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac201/6673214
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-08-22T12:59:34-04:00, https://www.cmttreatmentreport.com.
