E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Wang, Kun; Zhou, Lu; Jx, Wang; Wang, Yin; Sun, Tao; Zhao, Bing; Yang, Yadong; An, Tao; Long, Bo; Li, Na; Liu, Cui-Yun; Gong, Ying; Gao, Jin; Dong, Yanhan; Zhang, Jian; Li, Peifeng

doi:10.1038/ncomms8619

Cited by 87 publications

(67 citation statements)

References 50 publications

(56 reference statements)

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“…Similar result has also been reported in overexpressing miR-214 that targets MFN2 [24]. However, in cardiomyocytes, knocked down of E2F1 suppresses mitochondrial fragmentation by regulating miR-421 expression that targets PINK1, an important protein involved in mitophagy [54].Thus MFN2 is coregulated by transcription factor E2F1 and miRNA regulated by E2F1 forming closed network as described for other transcription factors and miRNA target genes [55,56]. It is known that miR-214 is activated by p53 by binding to the putative promoter [57]; whereas p53 is activated by E2F1 [40].…”

Section: Discussionsupporting

confidence: 84%

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

2019

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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.

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Section: Discussionsupporting

confidence: 84%

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

2019

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“…S3). This morphological discrepancy highlights that mitochondrial configuration in different cell types can be varied depending on their functions and histological backgrounds .…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial ubiquitin ligase plays an anti‐apoptotic role in cardiomyocytes by regulating mitochondrial fission

Wang

Aung

Prabhakar

et al. 2016

J Cellular Molecular Medi

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Apoptosis plays a critical role in the development of myocardial infarction. Cardiomyocytes are enriched with mitochondria and excessive mitochondrial fission can trigger cellular apoptosis. Recently, the mitochondrial ubiquitin ligase (MITOL), localized in the mitochondrial outer membrane, was reported to play an important role in the regulation of mitochondrial dynamics and apoptosis. However, the underlying mechanism of its action remains uncertain. The present study was aimed at uncovering the role of MITOL in the regulation of cardiomyocyte apoptosis. Our results showed that MITOL expression was up‐regulated in cardiomyocytes in response to apoptotic stimulation. Mitochondrial ubiquitin ligase overexpression blocked dynamin‐related protein 1 accumulation in the mitochondria, and attenuated the mitochondrial fission induced by hydrogen peroxide. Conversely, MITOL knockdown sensitized cardiomyocytes to undergo mitochondrial fission, resulting in subsequent apoptosis. These findings suggest that MITOL plays a protective role against apoptosis in cardiomyocytes, and may serve as a potential therapeutic target for apoptosis‐related cardiac diseases.

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“…In infarcted heart, PHB1 is downregulated by miR‐361, while antagonizing miR‐361 can inhibit mitochondrial fission, apoptosis and infarct sizes . The E2F1 is a key transcription factor in cell cycle of cardiomyocytes, which can induce mitochondrial fragmentation and apoptosis in cardiomyocytes through miR‐421 induced suppression of PTEN‐induced putative kinase 1(Pink1), a mitochondrial Ser/Thr kinase involved in protection against mitochondrial dysfunction . Interestingly, miR‐15b has a negative effect on cellular ATP level and mitochondrial integrity by inhibiting exchanger of ADP/ATP‐ADP‐ribosylation factor‐like2 (Arl2) located in mitochondria .…”

Section: Mirnas Modulate Mitochondrial Fission and Fusion Proteinsmentioning

confidence: 99%

Effects of miRNAs on myocardial apoptosis by modulating mitochondria related proteins

Zhao

Ponnusamy

Dong

et al. 2017

Clin Exp Pharma Physio

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E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

Cited by 87 publications

References 50 publications

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

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

The mitochondrial ubiquitin ligase plays an anti‐apoptotic role in cardiomyocytes by regulating mitochondrial fission

Effects of miRNAs on myocardial apoptosis by modulating mitochondria related proteins

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