Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts. Issue 2 (22nd August 2022)

• Record Type: Journal Article
• Authors: Zanfardino, Paola; Longo, Giovanna; Amati, Alessandro; Morani, Federica; Picardi, Ernesto; Girolamo, Francesco; Pafundi, Mariella; Cox, Sharon N; Manzari, Caterina; Tullo, Apollonia; Doccini, Stefano; Santorelli, Filippo M; Petruzzella, Vittoria
• Is Part Of: Human molecular genetics. Volume 32:Issue 2(2023)
• Page Start: 333
• Page End: 350
• Publication Date: 2022-08-22
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddac201
• Languages: English
• ISSNs: 0964-6906

Abstract

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 CMT2A MFN2 patient with an MFN2 650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity and autophagy/mitophagy, to tackle the multifaceted MFN 2 contribution to CMT2A pathogenesis. We found that MFN 2 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 CMT2A MFN2 fibroblasts. In conclusion, our evidence indicates that MFN 2 mutation can positively drive cell proliferation in CMT2A MFN2 fibroblasts.