MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

Abstract

Background Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC). Methods The expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses. Results MIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predicts poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to-mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells. Conclusions MIEF2 plays a critical role in the progression of OC and may serve as a valuable prognostic biomarker and therapeutic target in the treatment of this malignancy.

Mitochondrial Fission and Fusion in Tumor Progression to Metastasis

“…Fragmentation of mitochondria is widely thought to promote tumor progression ( Trotta and Chipuk, 2017 ). Indeed, fission promoting proteins—including DRP1 ( Zhao et al, 2013 ), MFF ( Seo et al, 2019 ), FIS1 ( Karimi et al, 2021 ; Soares et al, 2019 ), and MiD49 ( Zhao et al, 2020 )—are often found to have increased expression in cancer compared to normal adjacent tissues ( Table 2 ). In an elegant study, one group observed how changes in DRP1 and MFN1 expression drives invasive and migratory phenotypes ( Zhao et al, 2013 ).…”

“…Although it is generally accepted that mitochondrial fission is seen as promoting tumor growth and metastasis, the role of fission promoting receptor MiD49 (also known as MIEF2) in metastasis remains controversial. In ovarian cancer MiD49 mRNA and protein expression was increased in tumorigenic tissue in comparison to peritumor samples, and higher MiD49 expression correlated with worse overall and progression-free survival ( Zhao et al, 2020 ) ( Table 2 ). Indeed, ablation of MiD49 with siRNA increased mitochondrial length while reducing ovarian cancer cell growth, migration, invasion, tumor growth in and lung metastasis in vivo .…”

“…The proto-oncogene transcription factor, N-MYC, has been found to bind to promoter regions of DRP1 and control expression of this protein in Burkitt lymphoma and neuroblastoma cells, while not affecting other fusion proteins like MFN1 and OPA1 ( Agarwal et al, 2019 ). Other groups have shown regulation of DRP1 and MiD49 expression via different miRNA, which directly control invasive and migratory capacity of cancer cells ( Liang et al, 2020 ; Zhao et al, 2020 ). Thus, differential expression of select fission/fusion proteins could be explained by tumor type specific upstream regulatory factors, tumor microenvironment conditions, and hormone status ( Williams and Caino, 2018 ).…”

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

“…MiR-16-5p and 15b-5p coregulate ALDH1A3, which can inhibit the ubiquitination of PKM2 and regulate glycolysis to exert anticancer effects (Huang X. et al, 2021). In ovarian cancer, miR-424-5p inhibits mitochondrial elongation factor 2 (MIEF2), which regulates mitochondrial fission, inhibits glucose metabolism from oxidative phosphorylation to glycolysis, and inhibits tumor growth (Zhao et al, 2020). LIX1-like protein (LIX1L) promotes miR-21-3p, inhibits FBP1, reduces lactic acid production, and affects sugar metabolism to inhibit tumor growth (Zou et al, 2021) (Figure 1).…”

Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers

“…According to a previous study, miR-424-5p modulates glucose metabolism during tumor growth and metastasis [ 218 ]. However, recent studies also showed that it affects lipid metabolism in cancer cells.…”