E2F1 activates MFN2 expression by binding to the promoter and decreases mitochondrial fission and mitophagy in HeLa cells

Abstract

Mitofusin‐2 (MFN2) is primarily involved in mitochondrial fusion and participates in diverse biological processes. Several reports show that MFN2 is a target of different miRNAs; however, the transcriptional regulation of MFN2 has not been extensively studied. To gain insight into the transcriptional regulation of MFN2, we expressed E2F transcription factor 1 (E2F1) exogenously and observed that it increased the endogenous expression of MFN2 by binding to its putative promoter region. Although the levels of E2F1 were shown to vary during the cell cycle, the expression of MFN2 and its regulator SP1 did not change throughout the different phases, suggesting that E2F1 regulates MFN2 in a cell‐cycle‐independent manner. In the cell‐cycle phases, where the expression of E2F1 was reduced, SP1 might act in its place to regulate the expression of MFN2. We showed that E2F1 and SP1 are present as a complex on the promoter of MFN2 during the S‐phase as well as in E2F1 overexpressing cells, suggesting that they may regulate the expression of MFN2 synergistically. Furthermore, we found that E2F1 modulated mitochondrial fusion and mitophagy, likely through regulation of MFN2. Bioinformatic analysis revealed that several potential targets of E2F1 are localized in mitochondria and associated with autophagy. Collectively, these data identify the E2F1–MFN2 axis as a regulator of mitochondrial morphology and mitophagy, suggesting a potential therapeutic target for the treatment of mitochondrial disorders.

SNHG12/miR‐326/E2F1 feedback loop facilitates the progression of oral squamous cell carcinoma

“…For instance, E2F1 induces CDCA5 transcription to accelerate hepatocellular carcinoma cell proliferation through AKT pathway (Chen, Chen, et al, 2019). E2F1 enhances MFN2 expression to hamper mitochondrial fission and mitophagy in HeLa cells (Bucha, Mukhopadhyay, & Bhattacharyya, 2019). Nonetheless, the function of E2F1 as a transcription factor in OSCC remains largely unknown.…”

The XBP1-MARCH5-MFN2 Axis Confers ER Stress Resistance by Coordinating Mitochondrial Fission and Mitophagy in Melanoma

“…Besides, accumulative evidence has revealed that MFN2 was required for the induction of mitophagy by promoting depolarization-induced translocation of Parkin to the mitochondria [46,47]. However, some studies otherwise documented that MFN2 played a suppressive role in the activation of mitophagy by maintaining mitochondria-ER contacts and preventing the dissociation of mitochondria from the ER [25,26]. Our data showed that the down-regulation of MFN2 facilitated mitophagy via the induction of mitochondrial ssion under ER stress, supporting the suppressive effect of MFN2 on mitophagy.…”

“…S5a). MFN2 is a GTPase protein localized in the outer mitochondrial membrane as a crucial facilitator of mitochondrial fusion [25], and the reduction of MFN2 can be a trigger of mitophagy [26]. Therefore, we proposed that MFN2 down-regulation may be responsible for ER stress-induced mitochondrial ssion and mitophagy.…”

New relationship of E2F1 and BNIP3 with caveolin‐1 in lung cancer‐associated fibroblasts

“…Bucha et al . found that E2F1 modulated mitochondrial fusion and mitophagy, probably through regulation of MFN2. Bioinformatic analysis identified the E2F1–MFN2 axis as a regulator of mitochondrial morphology and mitophagy, which is the most direct evidence to show the relationship between E2F1 and mitophagy.…”