Apoptosis Repressor with Caspase Recruitment Domain Contributes to Chemotherapy Resistance by Abolishing Mitochondrial Fission Mediated by Dynamin-Related Protein-1

Jx, Wang; Li, Qian; Li, Peifeng

doi:10.1158/0008-5472.can-08-2962

Cited by 82 publications

(96 citation statements)

References 46 publications

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“…Drp1-mediated fission events primarily occur through multiple protein-protein interactions that form multimeric complexes (29). It was recently reported that PUMA is necessary for Drp1 to accumulate at the mitochondria; however, a direct interaction between PUMA and Drp1 remained unexplored (22).…”

Section: Discussionmentioning

confidence: 99%

“…Drp1 Translocation Is Mediated by PUMA After Loss of Pim. The BH3-only protein p53 up-regulated modulator of apoptosis (PUMA) is reported to be required for Drp1 accumulation to the mitochondria in HeLa cells (22). Proximity ligation assay (PLA) analysis with Drp1 and endogenous PUMA in NRCMs demonstrated protein-protein interaction at basal conditions (Fig.…”

Section: Drp1mentioning

confidence: 98%

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Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

121

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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pimdominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

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Section: Discussionmentioning

confidence: 99%

Section: Drp1mentioning

confidence: 98%

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

121

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“…Mitochondrial staining was carried as we and others described with modifications 4,47 . Briefly, cells were plated onto the coverslips coated with 0.01% poly-L-lysine.…”

Section: Methodsmentioning

confidence: 99%

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

et al. 2014

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Abnormal mitochondrial fission participates in the pathogenesis of many diseases. Long non-coding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the regulation of mitochondrial network is unclear. Here we report that a lncRNA, named cardiac apoptosis-related lncRNA (CARL), can suppress mitochondrial fission and apoptosis by targeting miR-539 and PHB2. The results show that PHB2 is able to inhibit mitochondrial fission and apoptosis. miR-539 is responsible for the dysfunction of PHB2 and regulates mitochondrial fission and apoptosis by targeting PHB2. Further, we show that CARL can act as an endogenous miR-539 sponge that regulates PHB2 expression, mitochondrial fission and apoptosis. Our present study reveals a model of mitochondrial fission regulation that is composed of CARL, miR-539 and PHB2. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.

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“…Mitochondrial staining was carried out as we and others described with modifications 3,52 . Briefly, cells were plated onto the coverslips coated with 0.01% poly-L-lysine.…”

Section: Methodsmentioning

confidence: 99%

miR-484 regulates mitochondrial network through targeting Fis1

et al. 2012

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mitochondria constantly undergo fusion and fission, two necessary processes for the maintenance of organelle fidelity. The abnormal mitochondrial fission participates in the pathogenesis of many diseases, but its regulation remains poorly understood. Here we show that miR-484 can suppress translation of mitochondrial fission protein Fis1, and inhibit Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. We demonstrate that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation. In exploring the underlying mechanism of miR-484 downregulation upon apoptosis, we observe that Foxo3a transactivates miR-484 expression. Foxo3a transgenic or knockout mice exhibit, respectively, a high or low level of miR-484 and a reduced or enhanced mitochondrial fission, apoptosis and myocardial infarction. our data reveal a model of mitochondrial fission regulation by a microRnA.

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Apoptosis Repressor with Caspase Recruitment Domain Contributes to Chemotherapy Resistance by Abolishing Mitochondrial Fission Mediated by Dynamin-Related Protein-1

Cited by 82 publications

References 46 publications

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

miR-484 regulates mitochondrial network through targeting Fis1

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