Dataset Information

Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) and mitostatin.

ABSTRACT: Tumor cell mitochondria are key biosynthetic hubs that provide macromolecules for cancer progression and angiogenesis. Soluble decorin protein core, hereafter referred to as decorin, potently attenuated mitochondrial respiratory complexes and mitochondrial DNA (mtDNA) in MDA-MB-231 breast carcinoma cells. We found a rapid and dynamic interplay between peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) and the decorin-induced tumor suppressor gene, mitostatin. This interaction stabilized mitostatin mRNA with concurrent accumulation of mitostatin protein. In contrast, siRNA-mediated abrogation of PGC-1?-blocked decorin-evoked stabilization of mitostatin. Mechanistically, PGC-1? bound MITOSTATIN mRNA to achieve rapid stabilization. These processes were orchestrated by the decorin/Met axis, as blocking the Met-tyrosine kinase or knockdown of Met abrogated these responses. Furthermore, depletion of mitostatin blocked decorin- or rapamycin-evoked mitophagy, increased vascular endothelial growth factor A (VEGFA) production, and compromised decorin-evoked VEGFA suppression. Collectively, our findings underscore the complexity of PGC-1?-mediated mitochondrial homeostasis and establish mitostatin as a key regulator of tumor cell mitophagy and angiostasis.

SUBMITTER: Neill T

PROVIDER: S-EPMC3931056 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitostatin.

Neill Thomas T Torres Annabel A Buraschi Simone S Owens Rick T RT Hoek Jan B JB Baffa Raffaele R Iozzo Renato V RV

The Journal of biological chemistry 20140108 8

Tumor cell mitochondria are key biosynthetic hubs that provide macromolecules for cancer progression and angiogenesis. Soluble decorin protein core, hereafter referred to as decorin, potently attenuated mitochondrial respiratory complexes and mitochondrial DNA (mtDNA) in MDA-MB-231 breast carcinoma cells. We found a rapid and dynamic interplay between peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the decorin-induced tumor suppressor gene, mitostatin. This interaction s ...[more]

PMID: 24403067

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Project description:OBJECTIVE Transcriptional peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1? activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1? activity. RESEARCH DESIGN AND METHODS We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1? activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. RESULTS Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1? deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1? deacetylation. CONCLUSIONS Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1? deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1?-independent mechanisms without mtDNA replication.

Project description:Hepatic peroxisomes are essential for lipid conversions that include the formation of mature conjugated bile acids, the degradation of branched chain fatty acids, and the synthesis of docosahexaenoic acid. Through unresolved mechanisms, deletion of functional peroxisomes from mouse hepatocytes (L-Pex5(-/-) mice) causes severe structural and functional abnormalities at the inner mitochondrial membrane. We now demonstrate that the peroxisomal and mitochondrial anomalies trigger energy deficits, as shown by increased AMP/ATP and decreased NAD(+)/NADH ratios. This causes suppression of gluconeogenesis and glycogen synthesis and up-regulation of glycolysis. As a consequence, L-Pex5(-/-) mice combust more carbohydrates resulting in lower body weights despite increased food intake. The perturbation of carbohydrate metabolism does not require a long term adaptation to the absence of functional peroxisomes as similar metabolic changes were also rapidly induced by acute elimination of Pex5 via adenoviral administration of Cre. Despite its marked activation, peroxisome proliferator-activated receptor α (PPARα) was not causally involved in these metabolic perturbations, because all abnormalities still manifested when peroxisomes were eliminated in a peroxisome proliferator-activated receptor α null background. Instead, AMP-activated kinase activation was responsible for the down-regulation of glycogen synthesis and induction of glycolysis. Remarkably, PGC-1α was suppressed despite AMP-activated kinase activation, a paradigm not previously reported, and they jointly contributed to impaired gluconeogenesis. In conclusion, lack of functional peroxisomes from hepatocytes results in marked disturbances of carbohydrate homeostasis, which are consistent with adaptations to an energy deficit. Because this is primarily due to impaired mitochondrial ATP production, these L-Pex5-deficient livers can also be considered as a model for secondary mitochondrial hepatopathies.

Dataset Information

Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) and mitostatin.

Publications

Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitostatin.

Similar Datasets

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