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Mfn2-mediated mitochondrial fusion promotes autophagy and suppresses ovarian cancer progression by reducing ROS through AMPK/mTOR/ERK signaling

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Abstract

Mitochondrial dynamics are balanced fission and fusion events that regulate mitochondrial morphology, and alteration in these events results in mitochondrial dysfunction and contributes to many diseases, including tumorigenesis. Ovarian cancer (OC) cells exhibit fragmented mitochondria, but the mechanism by which mitochondrial dynamics regulators contribute to OC is considerably less clear. Here, we elucidated the potential role of Mfn2-mediated mitochondrial fusion in OC and present evidence that genetic or pharmacological activation of Mfn2 leads to mitochondrial fusion and reduces ROS generation, which correlates with reduced cell proliferation, invasion, migration, and EMT in OC cells. Also, increased mitochondrial fusion promotes the F-actin remodeling, reduces lamellipodia formation, and thus reduces EMT. Increased expression of Mfn2 triggers AMPK, promotes autophagy, reduces ROS, and suppresses OC progression by downregulating  the p-mTOR (2481 and 2448) and p-ERK axis. OC patients with higher Mfn2 expression have better survival than those with lower Mfn2 levels. Our findings demonstrate that restoration of Mfn2-mediated mitochondrial fusion suppressed OC progression and suggest that this process could be a potential strategy in OC treatment.

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Data availability statement

The data supporting this study’s findings are available upon request from the corresponding author.

Abbreviations

ROS:

Reactive oxygen species

OC:

Ovarian cancer

Drp1:

Dynamin-related protein 1

EMT:

Epithelial-to-mesenchymal transition

AMPK:

AMP-activated protein kinase

mTOR:

Mammalian target of rapamycin

ERK:

Extracellular signal-regulated kinase

Opa1:

Optic atrophy1

Fis1:

Mitochondrial fission 1

ATP:

Adenosine triphosphate

mDivi-1:

Mitochondrial division inhibitor 1

CDK1:

Cyclin-dependent kinase 1

PCNA:

Proliferating cell nuclear antigen

H2O2 :

Hydrogen peroxide

PFS:

Progression-free survival

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Acknowledgements

SK is thankful to DST SERB for awarding the core research grant, DBT for granting the Ramalingaswami Re-entry fellowship, and the Indian Institute of Science Education & Research (IISER) Tirupati for their support. The authors thank Dr. Ravichandra S. Davargaon, and Urja Kamdar for their technical assistance.

Funding

This work was supported by DST-SERB (CRG/2019/002104), Ramalingaswami re-entry fellowship, DBT (BT/RLF/Re-entry/13/2016), and IISER Tirupati funds to SK. RA is thankful to IISER Tirupati for the fellowship.

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  1. Division of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Karkambadi Road, Rami Reddy Nagar, Mangalam, Tirupati, Andhra Pradesh, 517507, India

    Rahail Ashraf & Sanjay Kumar

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RA contributed to methodology, formal analysis, investigation, and data curation. SK was involved in conceptualization, methodology, writing–original draft, supervision, project administration, and funding acquisition.

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Correspondence to Sanjay Kumar.

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18_2022_4595_MOESM1_ESM.png

Supplementary file1 Supplementary Figure 1A: Western blot analysis determines the expression of Cyclin D1, PCNA, Beclin1, Vimentin, and β-Actin in A2780 cells after transient transfection with two Mfn2 siRNA as indicated. (1B) Cell death assay by staining with PI using FACS (BD) in two OC cells. (PNG 1459 KB)

18_2022_4595_MOESM2_ESM.png

Supplementary file2 Supplementary Figure 2A: Microscopy images of wound closure after Mfn2 silencing in SKOV-3 cells with or without NAC treatment (20 mM for 12 h). The percentage of a reduced area or wound closure in the captured images was calculated using Image J at each time point. NAC treatment reduces the cell migration. si, small interfering RNAs; NAC, N-acetyl cysteine. Data were represented as mean ± SD. Differences among groups were considered significant *p < 0.05, ** p < 0.01 and *** p < 0.001 (PNG 9316 KB)

18_2022_4595_MOESM3_ESM.png

Supplementary file3 Supplementary Figure 3A and Ai: Western blot analysis and quantification demonstrated Mfn2 overexpression in two OC cells was positively correlated with ATG5 and Beclin-1 expression. In contrast, silencing Mfn2 reduces the expression of autophagic markers. (3B and C) Representative confocal images of OC cells indicate a correlation between Mfn2 expression and ATG5. Both cell types were transiently transfected with Mfn2 siRNA or overexpression plasmid stained with DAPI and ATG5 antibodies. DAPI is dark blue, and ATG5 is green. (3B) Scale bar 25 µm, (3C) Scale bar 10 µm. Data were represented as mean ± SD. Differences among groups were considered significant *p < 0.05, ** p < 0.01 and *** p < 0.001 (PNG 9141 KB)

18_2022_4595_MOESM4_ESM.png

Supplementary file4 Supplementary Figure 4A: Representative confocal images of A2780 cells indicates a correlation between Mfn2 expression and p-ERK. Cells were transiently transfected with Mfn2 siRNA or overexpression plasmid stained with DAPI, Mfn2, and p-ERK antibodies. DAPI: dark blue, Mfn2: red, and p-ERK: green. Scale bar 10 µm. (4B) Graphs display the relative cell proliferation analyzed by MTT assay after Mfn2 silencing in OC cells with or without NAC treatment (20 mM for 12 h). NAC treatment notably reduced the proliferation of OC cells compared to the silenced Mfn2 cells without NAC treatment. si, small interfering RNAs, NAC, N-acetyl cysteine. Immunoblotting analysis showed that NAC treatment reduces OC cell proliferation by reducing PCNA and Cyclin D1 expression (PNG 7202 KB)

Supplementary file5 (DOCX 16 KB)

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Ashraf, R., Kumar, S. Mfn2-mediated mitochondrial fusion promotes autophagy and suppresses ovarian cancer progression by reducing ROS through AMPK/mTOR/ERK signaling. Cell. Mol. Life Sci. 79, 573 (2022). https://doi.org/10.1007/s00018-022-04595-6

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  • DOI: https://doi.org/10.1007/s00018-022-04595-6

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