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Tsc and autophagy

Alessandro Magini, Alice Polchi, Danila Di Meo, Giuseppina Mariucci, Krizia Sagini, Federico De Marco, Tommaso Cassano, Stefano Giovagnoli, Diego Dolcetta, Carla Emiliani
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs)...
June 14, 2017: Human Molecular Genetics
Daniela Bakula, Amelie J Müller, Theresia Zuleger, Zsuzsanna Takacs, Mirita Franz-Wachtel, Ann-Katrin Thost, Daniel Brigger, Mario P Tschan, Tancred Frickey, Horst Robenek, Boris Macek, Tassula Proikas-Cezanne
Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes...
May 31, 2017: Nature Communications
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Mustafa Sahin
Constitutive activation of the MTOR pathway is a key feature of defects in the tuberous sclerosis complex and other genetic neurodevelopmental diseases, collectively referred to as MTORopathies. MTORC1 hyperactivity promotes anabolic cell functions such as protein synthesis, yet at the same time catabolic processes such as macroautophagy/autophagy are suppressed. Mitochondria are major substrates of autophagy; however, their role in MTORopathies remains largely undefined. Here, we review our recent study showing that several aspects of mitochondrial function, dynamics and turnover are critically impaired in neuronal models of TSC...
April 3, 2017: Autophagy
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Alessia Di Nardo, Daria Turner, Tommy L Lewis, Christopher Conrad, Jonathan M Rothberg, Jonathan O Lipton, Stefan Kölker, Georg F Hoffmann, Min-Joon Han, Franck Polleux, Mustafa Sahin
Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC...
October 18, 2016: Cell Reports
Piotr T Filipczak, Cindy Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multiorgan disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart, and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
December 15, 2016: Cancer Research
Barbara Kathage, Sebastian Gehlert, Anna Ulbricht, Laura Lüdecke, Victor E Tapia, Zacharias Orfanos, Daniela Wenzel, Wilhelm Bloch, Rudolf Volkmer, Bernd K Fleischmann, Dieter O Fürst, Jörg Höhfeld
The cochaperone BAG3 is a central protein homeostasis factor in mechanically strained mammalian cells. It mediates the degradation of unfolded and damaged forms of the actin-crosslinker filamin through chaperone-assisted selective autophagy (CASA). In addition, BAG3 stimulates filamin transcription in order to compensate autophagic disposal and to maintain the actin cytoskeleton under strain. Here we demonstrate that BAG3 coordinates protein synthesis and autophagy through spatial regulation of the mammalian target of rapamycin complex 1 (mTORC1)...
January 2017: Biochimica et Biophysica Acta
Ana García-Aguilar, Carlos Guillén, Mark Nellist, Alberto Bartolomé, Manuel Benito
There is a growing evidence of the role of protein acetylation in different processes controlling metabolism. Sirtuins (histone deacetylases nicotinamide adenine dinucleotide-dependent) activate autophagy playing a protective role in cell homeostasis. This study analyzes tuberous sclerosis complex (TSC2) lysine acetylation, in the regulation of mTORC1 signaling activation, autophagy and cell proliferation. Nicotinamide 5mM (a concentration commonly used to inhibit SIRT1), increased TSC2 acetylation in its N-terminal domain, and concomitantly with an augment in its ubiquitination protein status, leading to mTORC1 activation and cell proliferation...
November 2016: Biochimica et Biophysica Acta
A Venkatesh, S Ma, C Punzo
Understanding the mechanisms that contribute to secondary cone photoreceptor loss in retinitis pigmentosa (RP) is critical to devise strategies to prolong vision in this neurodegenerative disease. We previously showed that constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1), by loss of its negative regulator the tuberous sclerosis complex protein 1 (Tsc1; also known as Hamartin), was sufficient to promote robust survival of nutrient-stressed cones in two mouse models of RP by improving glucose uptake and utilization...
June 30, 2016: Cell Death & Disease
Elizabeth P Henske, Sergiusz Jóźwiak, J Christopher Kingswood, Julian R Sampson, Elizabeth A Thiele
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability...
May 26, 2016: Nature Reviews. Disease Primers
Manabu Taneike, Kazuhiko Nishida, Shigemiki Omiya, Elham Zarrinpashneh, Tomofumi Misaka, Rika Kitazume-Taneike, Ruth Austin, Minoru Takaoka, Osamu Yamaguchi, Michael J Gambello, Ajay M Shah, Kinya Otsu
Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice...
2016: PloS One
Tania Campos, Javiera Ziehe, Francisco Fuentes-Villalobos, Orlando Riquelme, Daniela Peña, Rodrigo Troncoso, Sergio Lavandero, Violeta Morin, Roxana Pincheira, Ariel F Castro
Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment...
June 2016: Biochimica et Biophysica Acta
Durga Nand Tripathi, Cheryl Lyn Walker
Peroxisomes participate in lipid metabolism, and are a major source of ROS in the cell. Their importance in cellular energy balance and redox homeostasis is well-established, as is the need to maintain peroxisome homeostasis to prevent pathologies associated with too few, or too many, of these organelles. How cells regulate peroxisome number has remained somewhat elusive. Recently, the tumor suppressors ATM and TSC, which regulate mTORC1 signaling, have been localized to peroxisomes. When activated by peroxisomal ROS, ATM signals to TSC to repress mTORC1 signaling and increase autophagic flux in cells, and also phosphorylates the peroxisomal protein PEX 5 to target peroxisomes for selective autophagy (pexophagy), providing a mechanism for regulation of peroxisomal homeostasis using ROS as a rheostat...
April 2016: Current Opinion in Cell Biology
Duncan McVey, Michael Aronov, Giovanni Rizzi, Alexis Cowan, Charo Scott, John Megill, Reb Russell, Boaz Tirosh
The kinase mTOR operates in two cellular complexes, mTORC1 and mTORC2. mTORC1 adjusts metabolic activity according to external growth conditions and nutrients availability. When conditions are prosperous, mTOR facilitates protein and lipid biosyntheses and inhibits autophagy, while under metabolic constraints, however, its attenuation induces a catabolic program, energy preservation and autophagy. CHO is a key cell line for manufacturing of biologics owing to its remarkable ability to grow to high densities and maintain protein production and secretion for extended times...
September 2016: Biotechnology and Bioengineering
You-Zhi Xu, Yong-Huai Li, Wen-Jie Lu, Kun Lu, Chun-Ting Wang, Yan Li, Hong-Jun Lin, Li-Xin Kan, Sheng-Yong Yang, Si-Ying Wang, Ying-Lan Zhao
Cancer cells activate autophagy in response to anticancer therapies. Autophagy induction is a promising therapeutic approach to treat cancer. In a previous study, YL4073 inhibited the growth of liver cancer and induced liver cancer cell apoptosis. Here, we demonstrated the anticancer activity and specific mechanisms of YL4073 in Lewis lung carcinoma LL/2 cells. Our results show that YL4073-induced autophagy was followed by apoptotic cell death. The anticancer and autophagy stimulating efficacy was confirmed by several factors, including the appearance of autophagic vacuoles, formation of acidic vesicular organelles, recruitment of microtubule-associated protein 1 light chain 3 II (LC3-II) to the autophagosomes, conversion and cleavage of LC3-I to LC3-II, upregulation of Beclin 1 expression, and formation of the Atg12-Atg5 conjugate in LL/2 cells after YL4073 treatment for 24 or 48 h...
April 2016: Oncology Reports
Meijuan Ma, Liqiang Song, Hao Yan, Min Liu, Le Zhang, Ying Ma, Jian Yuan, Jianhua Hu, Zhaole Ji, Rongqing Zhang, Congye Li, Haichang Wang, Ling Tao, Yingmei Zhang, Yan Li
After decades of indolent progression, atherosclerosis may cause unheralded events, such as myocardial infarction, acute coronary syndrome and stroke due to sudden rupture of atherosclerotic plaques, and pharmacologically modulating plaque stability would reduce the risk of cardiovascular diseases. Endoplasmic reticulum stress (ERS) is responsible for the vulnerability of plaques. However, the underlying mechanism has not been fully elucidated. In this work, ApoE(-/-) mice underwent perivascular carotid collar placement surgeries or sham operations were given higher (3...
January 15, 2016: Biochemical Pharmacology
Shiyun Chen, Yueshan Piao, Yongjuan Fu, Zhuo Li, Cuicui Liu, Dehong Lu
OBJECTIVE: To study the expression of autophagy-related proteins (Beclin-1, LC3 and p62) in brain tissue with malformations of cortical development and related molecular pathogenesis. METHODS: The brain tissue of 18 cases with epileptogenic foci resection, including 6 cases of tuberous sclerosis complex (TSC), 6 cases of focal cortical dysplasia type IIb (FCD IIb) and 6 cases of focal cortical dysplasia type I (FCD I), were retrieved. Immunohistochemical study for Beclin-1, LC3 and p62 proteins was performed...
May 2015: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
Yang Zhao, Ming-Ming Zhao, Yan Cai, Ming-Fei Zheng, Wei-Liang Sun, Song-Yang Zhang, Wei Kong, Jun Gu, Xian Wang, Ming-Jiang Xu
Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis...
October 2015: Kidney International
Mari Wataya-Kaneda
Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is a member of the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 has emerged as a central regulator of cellular metabolism, cell proliferation, cellular differentiation, autophagy and immune response regulation. In contrast to mTORC1, mTORC2, which is not well understood, participates in cell survival and the regulation of actin and cytokeratin organization...
August 2015: Journal of Dermatological Science
Yinan Zhang, Brendan D Manning
Defects in the maintenance of protein homeostasis, or proteostasis, has emerged as an underlying feature of a variety of human pathologies, including aging-related diseases. Proteostasis is achieved through the coordinated action of cellular systems overseeing amino acid availability, mRNA translation, protein folding, secretion, and degradation. The regulation of these distinct systems must be integrated at various points to attain a proper balance. In a recent study, we found that the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway, well known to enhance the protein synthesis capacity of cells while concordantly inhibiting autophagy, promotes the production of more proteasomes...
2015: Cell Cycle
Dong Liu, Yongqing Zhang, Robert Gharavi, Hee Ra Park, Jaewon Lee, Sana Siddiqui, Richard Telljohann, Matthew R Nassar, Roy G Cutler, Kevin G Becker, Mark P Mattson
Mitochondrial metabolism is highly responsive to nutrient availability and ongoing activity in neuronal circuits. The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown. Mild mitochondrial uncoupling enhances cellular energy expenditure in mitochondria and can be induced with 2,4-dinitrophenol (DNP), a proton ionophore previously used for weight loss. We found that DNP treatment reduces mitochondrial membrane potential, increases intracellular Ca(2+) levels and reduces oxidative stress in cerebral cortical neurons...
August 2015: Journal of Neurochemistry
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