Mitofusin 2-Deficiency Suppresses Cell Proliferation through Disturbance of Autophagy

Ding, Yanhong; Gao, Han; Zhao, Lifang; Wang, Xian; Zheng, Ming

doi:10.1371/journal.pone.0121328

Cited by 45 publications

(31 citation statements)

References 46 publications

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“…Most recently Ding et al (2015) have shown that knockdown of the Mfn2 gene with shRNA inhibited not only oxygen consumption, but also glycolysis and cell proliferation and reduced cellular ATP content. These data probably confirm the differences between cellular response to acute and persistent deficiency of mitofusin 2 [ 31 ]. Our data shown here indicate that stable depletion of Mfn2 gene induces adaptive processes counteracting disorganization of cell metabolism and function and preventing severe abnormalities.…”

Section: Discussionsupporting

confidence: 66%

Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells

et al. 2015

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Mitofusin 2 (Mfn2), mitochondrial outer membrane protein which is involved in rearrangement of these organelles, was first described in pathology of hypertension and diabetes, and more recently much attention is paid to its functions in Charcot-Marie-Tooth type 2A neuropathy (CMT2A). Here, cellular energy metabolism was investigated in mouse embryonic fibroblasts (MEF) differing in the presence of the Mfn2 gene; control (MEFwt) and with Mfn2 gene depleted MEFMfn2-/-. These two cell lines were compared in terms of various parameters characterizing mitochondrial bioenergetics. Here, we have shown that relative rate of proliferation of MEFMfn2-/- cells versus control fibroblasts depend on serum supplementation of the growth media. Moreover, MEFMfn2-/- cells exhibited significantly increased respiration rate in comparison to MEFwt, regardless of serum supplementation of the medium. This effect was correlated with increased level of mitochondrial markers (TOM20 and NAO) as well as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein levels and unchanged total ATP content. Interestingly, mitochondrial DNA content in MEFMfn2-/- cells was not reduced. Fundamentally, these results are in contrast to a commonly accepted belief that mitofusin 2 deficiency inevitably results in debilitation of mitochondrial energy metabolism. However, we suggest a balance between negative metabolic consequences of mitofusin 2 deficiency and adaptive processes exemplified by increased level of PGC-1α and TFAM transcription factor which prevent an excessive depletion of mtDNA and severe impairment of cell metabolism.

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Section: Discussionsupporting

confidence: 66%

Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells

et al. 2015

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“…Mitofusin2 (Mfn2) is a guanosine triphosphatase (GTPase) dynamin-like protein of the outer mitochondrial membrane, and mutations in genes that encode Mfn2 can be associated with neurological disorders [13]. It is also involved in various pathologic conditions, ranging from neurodegeneration to diabetes and obesity, and different crucial cellular processes, including cell proliferation, survival or death, and maintenance of mitochondrial deoxyribonucleic acid stability [14]. As an important regulator of tissue fibrosis and cell proliferation, Mfn2 is a direct target gene of miRNA-214, which negatively regulates Mfn2 expression by translational inhibition [15].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-214 Affects Fibroblast Differentiation of Adipose-Derived Mesenchymal Stem Cells by Targeting Mitofusin-2 during Pelvic Floor Dysfunction in SD Rats with Birth Trauma

Wu¹,

Jiang²,

Chen³

et al. 2017

Cell Physiol Biochem

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Background/Aims: This study investigated whether microRNA-214 (miR-214) targets mitofusin-2 (Mfn2) in the process of fibroblast differentiation of adipose-derived mesenchymal stem cells (ADMSCs) during pelvic floor dysfunction (PFD) in Sprague Dawley (SD) rats with birth trauma. Methods: The ADMSCs were isolated from 4-6 week male SD rats (n = 20) and were cultured and divided into the blank, miR-214 mimic negative control (NC), miR-214 mimic, miR-214 inhibitor NC, miR-214 inhibitor, empty vector, Mfn2 over-expression and miR-214 + Mfn2 over-expression groups. Fibroblast differentiation of ADMSCs was measured with immunocytochemistry and immunofluorescence methods. The expression of miR-214 and the mRNA and protein expression of Mfn2, FSP1, Collagen I, Collagen III, Elastin, LOX, Fibulin-5, PPAR-γ and Runx2 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. A dual-luciferase reporter assay was performed to confirm whether Mfn2 was the target gene of miR-214. Results: During ADMSC differentiation into fibroblasts, miR-214 expression was up-regulated, but the expression of Mfn2 was down-regulated. Fibroblast differentiation of ADMSCs was promoted in the miR-214 mimic group but was inhibited in the miR-214 inhibitor and Mfn2 over-expression groups. The expression of Mfn2 was decreased, but the expression of FSP1, Collagen I, Collagen III, Elastin, LOX, Fibulin-5, PPAR-γ or Runx2 was increased in the miR-214 mimic group; the miR-214 inhibitor group and Mfn2 over-expression group exhibited the opposite results. Mfn2 was the target gene of miR-214. Conclusions: The study provided strong evidence that miR-214 could promote fibroblast differentiation of ADMSCs by down-regulating Mfn2 to improve PFD in SD rats with birth trauma.

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“…Interestingly, a recent report indicated that defect of mitochondrial fusion protein Mfn2 impaired autophagy-induced degradation, subsequently decreasing mitochondrial oxygen consumption rate and cell glycolysis, reducing ATP production, and suppressing cell proliferation. 73 Therefore, FSH-induced autophagy is a regulatory mechanism that ensure the order and timing of cell cycle transition by mitophagy activation through the PINK1-Parkin pathway ( Figure 8h ), which may help reducing follicle atresia and GC apoptosis. 74 …”

Section: Discussionmentioning

confidence: 99%

Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1α in mouse granulosa cells

Zhou

Wang

et al. 2017

Cell Death Dis

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Recent studies reported the important role of autophagy in follicular development. However, the underlying molecular mechanisms remain elusive. In this study, we investigated the effect of follicle-stimulating hormone (FSH) on mouse granulosa cells (MGCs). Results indicated that autophagy was induced by FSH, which is known to be the dominant hormone regulating follicular development and granulosa cell (GC) proliferation. The activation of mammalian target of rapamycin (mTOR), a master regulator of autophagy, was inhibited during the process of MGC autophagy. Moreover, MHY1485 (an agonist of mTOR) significantly suppressed autophagy signaling by activating mTOR. The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was increased after FSH treatment. Blocking hypoxia-inducible factor 1-alpha attenuated autophagy signaling. In vitro, CoCl2-induced hypoxia enhanced cell autophagy and affected the expression of beclin1 and BCL2/adenovirus E1B interacting protein 3 (Bnip3) in the presence of FSH. Knockdown of beclin1 and Bnip3 suppressed autophagy signaling in MGCs. Furthermore, our in vivo study demonstrated that the FSH-induced increase in weight was significantly reduced after effectively inhibiting autophagy with chloroquine, which was correlated with incomplete mitophagy process through the PINK1-Parkin pathway, delayed cell cycle, and reduced cell proliferation rate. In addition, chloroquine treatment decreased inhibin alpha subunit, but enhanced the expression of 3 beta-hydroxysteroid dehydrogenase. Blocking autophagy resulted in a significantly lower percentage of antral and preovulatory follicles after FSH stimulation. In conclusion, our results indicate that FSH induces autophagy signaling in MGCs via HIF-1α. In addition, our results provide evidence that autophagy induced by FSH is related to follicle development and atresia.

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Mitofusin 2-Deficiency Suppresses Cell Proliferation through Disturbance of Autophagy

Cited by 45 publications

References 46 publications

Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells

Mitofusin 2 Deficiency Affects Energy Metabolism and Mitochondrial Biogenesis in MEF Cells

MicroRNA-214 Affects Fibroblast Differentiation of Adipose-Derived Mesenchymal Stem Cells by Targeting Mitofusin-2 during Pelvic Floor Dysfunction in SD Rats with Birth Trauma

Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1α in mouse granulosa cells

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