PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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Bifidobacterium animalis subsp. lactis A6 Alleviates Obesity Associated with Promoting Mitochondrial Biogenesis and Function of Adipose Tissue in Mice

Molecules ◽

10.3390/molecules25071490 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1490

Author(s):

Yanxiong Huo ◽

Xuhong Lu ◽

Xiaoyu Wang ◽

Xifan Wang ◽

Lingli Chen ◽

...

Keyword(s):

Mitochondrial Biogenesis ◽

Uncoupling Protein ◽

Positive Control ◽

Peroxisome Proliferator ◽

Adipose Tissues ◽

Peroxisome Proliferator Activated Receptor ◽

Bifidobacterium Animalis ◽

Mitochondrial Biosynthesis ◽

And Function ◽

Estrogen Related Receptor

Probiotics are widely known for their health benefits. Mitochondrial dysfunction is related to obesity. The aim of this study was to illuminate whether Bifidobacterium animalis subsp. lactis A6 (BAA6) could improve obesity due to increased mitochondrial biogenesis and function of adipose tissues. Four-week-old male C57BL/6 mice were fed with a high-fat diet (HFD) for 17 weeks. For the final eight weeks, the HFD group was divided into three groups including HFD, HFD with BAA6 (HFD + BAA6 group), and HFD with Akkermansia muciniphila (AKK) (HFD + AKK group as positive control). The composition of the microbiota, serum lipopolysaccharides (LPS), and mitochondrial biosynthesis and function of epididymal adipose tissues were measured. Compared with the HFD group, body weight, relative fat weight, the relative abundance of Oscillibacter and Bilophila, and serum LPS were significantly decreased in the HFD + BAA6 and HFD + AKK groups (p < 0.05). Furthermore, the addition of BAA6 and AKK increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (by 21.53- and 18.51-fold), estrogen-related receptor α (ERRα) (by 2.83- and 1.24-fold), and uncoupling protein-1 (UCP-1) (by 1.51- and 0.60-fold) in epididymal adipose tissues. Our results suggest that BAA6 could improve obesity associated with promoting mitochondrial biogenesis and function of adipose tissues in mice.

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Peroxisome proliferator-activated receptor-gamma activation attenuates diabetic cardiomyopathy via regulation of the TGF-β/ERK pathway and epithelial-to-mesenchymal transition

Life Sciences ◽

10.1016/j.lfs.2018.09.004 ◽

2018 ◽

Vol 213 ◽

pp. 269-278 ◽

Cited By ~ 6

Author(s):

Xiu-lian Yan ◽

Yuan-yuan Wang ◽

Zhong-Fei Yu ◽

Mi-mi Tian ◽

Hui Li

Keyword(s):

Diabetic Cardiomyopathy ◽

Epithelial To Mesenchymal Transition ◽

Peroxisome Proliferator ◽

Erk Pathway ◽

Gamma Activation ◽

Peroxisome Proliferator Activated Receptor ◽

Mesenchymal Transition

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Loss of PGC-1α in RPE induces mesenchymal transition and promotes retinal degeneration

Life Science Alliance ◽

10.26508/lsa.201800212 ◽

2019 ◽

Vol 2 (3) ◽

pp. e201800212 ◽

Cited By ~ 7

Author(s):

Mariana Aparecida Brunini Rosales ◽

Daisy Y Shu ◽

Jared Iacovelli ◽

Magali Saint-Geniez

Keyword(s):

Visual Processing ◽

Epithelial To Mesenchymal Transition ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Conditional Knockout ◽

Age Related Macular Degeneration ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Mesenchymal Transition ◽

Age Related

The retinal pigment epithelium (RPE) supports visual processing and photoreceptor homeostasis via energetically demanding cellular functions. Here, we describe the consequences of repressing peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α), a master regulator of mitochondrial function and biogenesis, on RPE epithelial integrity. The sustained silencing of PGC-1α in differentiating human RPE cells affected mitochondria/autophagy function, redox state, and impaired energy sensor activity ultimately inducing epithelial to mesenchymal transition (EMT). Adult conditional knockout of PGC-1 coactivators in mice resulted in rapid RPE dysfunction and transdifferentiation associated with severe photoreceptor degeneration. RPE anomalies were characteristic of autophagic defect and mesenchymal transition comparable with the ones observed in age-related macular degeneration. These findings demonstrate that PGC-1α is required to maintain the functional and phenotypic status of RPE by supporting the cells’ oxidative metabolism and autophagy-mediated repression of EMT.

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SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/4602715 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 41

Author(s):

Sai Ma ◽

Jing Feng ◽

Ran Zhang ◽

Jiangwei Chen ◽

Dong Han ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Mitochondrial Biogenesis ◽

Mitochondrial Dynamics ◽

Diabetic Patients ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Respiratory Factor ◽

Beneficial Effects ◽

Mitochondrial Regulation ◽

And Function

Background. Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM. Methods and Results. Cardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM). Conclusions. Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM.

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Combination of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist and PPAR Gamma Co-Activator 1α (PGC-1α) Activator Ameliorates Cognitive Deficits, Oxidative Stress, and Inflammation in Rodent Model of Parkinson's Disease

Current Neurovascular Research ◽

10.2174/1567202619666211217140954 ◽

2021 ◽

Vol 19 ◽

Author(s):

Nihar Ranjan Das ◽

Bhupesh Vaidya ◽

Pragyanshu Khare ◽

Mahendra Bishnoi ◽

Shyam Sunder Sharma

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Lipoic Acid ◽

Mitochondrial Biogenesis ◽

Cognitive Deficits ◽

Ppar Gamma ◽

Peroxisome Proliferator ◽

Alpha Lipoic Acid ◽

Peroxisome Proliferator Activated Receptor ◽

Pparγ Agonist

Background: PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson’s disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. Objective: In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Results: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. Conclusion: Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.

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Interferon-Stimulated Gene ISG12b1 Inhibits Adipogenic Differentiation and Mitochondrial Biogenesis in 3T3-L1 Cells

Endocrinology ◽

10.1210/en.2008-0727 ◽

2008 ◽

Vol 150 (3) ◽

pp. 1217-1224 ◽

Cited By ~ 21

Author(s):

Bing Li ◽

Jonghyun Shin ◽

Kichoon Lee

Keyword(s):

Mitochondrial Biogenesis ◽

Adipogenic Differentiation ◽

Peroxisome Proliferator ◽

Mitochondrial Transcription ◽

Peroxisome Proliferator Activated Receptor ◽

And Function ◽

Adipocyte Development

Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-γ (PPARγ), and CCAAT/enhancer-binding protein-α (C/EBPα). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARγ and PPARα agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases. ISG12b1 is predominantly expressed in adipocytes and dramatically induced at the terminal stage of adipogenesis. Functionally, mitochondria-localized ISG12b1 inhibits adipogenic differentiation and mitochondria biogenesis.

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Regulation of mitochondrial biogenesis

Essays in Biochemistry ◽

10.1042/bse0470069 ◽

2010 ◽

Vol 47 ◽

pp. 69-84 ◽

Cited By ~ 356

Author(s):

François R. Jornayvaz ◽

Gerald I. Shulman

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Biogenesis ◽

Molecular Mechanisms ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Respiratory Factor ◽

Mitochondrial Transcription Factor ◽

Nuclear Respiratory Factor 1 ◽

And Function ◽

Amp Activated Protein Kinase

Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer’s disease. PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1α itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.

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