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Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression.

ABSTRACT: Mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA replication and transcription, which are essential for mitochondrial biogenesis. Previous studies reported that depleting mitochondrial functions by genetic deletion of TFAM impaired autophagic activities. However, the underlying mechanisms remain largely unknown. In the current study, we identified that knockdown of TFAM repressed the synthesis of autophagy bio-marker LC3-II in tumor cells and decreased the expression of phosphatidyl-serine decarboxylase (PISD). Besides, downregulation of PISD with siRNA reduced the level of LC3-II, indicating that depletion of TFAM retarded autophagy via inhibiting PISD expression. Furthermore, it was found that the tumor repressor p53 could stimulate the transcription and expression of PISD by binding the PISD enhancer. Additionally, the protein stability and transcriptional activity of p53 in TFAM knockdown tumor cells was attenuated, and this was associated with decreased acetylation, especially the acetylation of lysine 382 of p53. Finally, we identified that TFAM knockdown increased the NAD+/NADH ratio in tumor cells. This led to the upregulation of Sirtuin1 (SIRT1), a NAD-dependent protein deacetylase, to deacetylate p53 and attenuated its transcriptional activation on PISD. In summary, our study discovered a new mechanism regarding disturbed autophagy in tumor cells with mitochondrial dysfunction due to the depletion of TFAM.

SUBMITTER: Jiang X

PROVIDER: S-EPMC7072172 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression.

Jiang Xu X Wang Jun J

Cancers 20200220 2

Mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA replication and transcription, which are essential for mitochondrial biogenesis. Previous studies reported that depleting mitochondrial functions by genetic deletion of TFAM impaired autophagic activities. However, the underlying mechanisms remain largely unknown. In the current study, we identified that knockdown of TFAM repressed the synthesis of autophagy bio-marker LC3-II in tumor cells and decreased the expression ...[more]

PMID: 32093281

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Project description:Aims:SUMOylation is a post-translational modification that plays a crucial role in the cellular stress response. We aimed to demonstrate whether and how the SUMO E2 conjugation enzyme Ubc9 affects acute myocardial ischemic (MI) injury. Methods and Results:Adenovirus expressing Ubc9 was administrated by multipoint injection in the border zone of heart immediately after MI in C57BL/6 mice. Neonatal rat cardiomyocytes (NRCMs) were also infected, followed by oxygen and glucose deprivation (OGD). In vivo, Ubc9 adenovirus-injected mice showed decreased cardiomyocyte apoptosis, reduced myocardial fibrosis, and improved cardiac function post-MI. In vitro, overexpression of Ubc9 decreased cardiomyocyte apoptosis, whereas silence of Ubc9 showed the opposite results during OGD. We next found that Ubc9 significantly decreased the accumulation of autophagy marker p62/SQSTM, while the LC3 II level hardly changed. When in the presence of bafilomycin A1 (BAF), the Ubc9 adenovirus plus OGD group presented a higher level of LC3 II and GFP-LC3 puncta than the OGD group. Moreover, the Ubc9 adenovirus group displayed increased numbers of yellow plus red puncta and a rising ratio of red to yellow puncta on the mRFP-GFP-LC3 fluorescence assay, indicating that Ubc9 induces an acceleration of autophagic flux from activation to degradation. Mechanistically, Ubc9 upregulated SUMOylation of the core proteins Vps34 and Beclin1 in the class III phosphatidylinositol 3-kinase (PI3K-III) complexes and boosted the protein assembly of PI3K-III complex I and II under OGD. Moreover, the colocalization of Vps34 with autophagosome marker LC3 or lysosome marker Lamp1 was augmented after Ubc9 overexpression, indicating a positive effect of Ubc9-boosted protein assembly of the PI3K-III complexes on autophagic flux enhancement. Conclusions:We uncovered a novel role of Ubc9 in protecting cardiomyocytes from ischemic stress via Ubc9-induced SUMOylation, leading to increased PI3K-III complex assembly and autophagy-positioning. These findings may indicate a potential therapeutic target, Ubc9, for treatment of myocardial ischemia.

Dataset Information

Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression.

Publications

Knockdown of TFAM in Tumor Cells Retarded Autophagic Flux through Regulating p53 Acetylation and PISD Expression.

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