Ablation of TSC2 Enhances Insulin Secretion by Increasing the Number of Mitochondria through Activation of mTORC1

Koyanagi, Maki; Asahara, Shun‐ichiro; Matsuda, Tomokazu; Hashimoto, Naoko; Shigeyama, Yutaka; Shibutani, Yuki; Kanno, Ayumi; Fuchita, Megumi; Mikami, Takuma; Hosooka, Tetsutya; Inoue, Hiroshi; Matsumoto, Michihiro; Koike, Masato; Uchiyama, Yasuo; Noda, Tetsuo; Seino, Susumu; Kasuga, Masato; Kido, Yoshiaki

doi:10.1371/journal.pone.0023238

Cited by 53 publications

(50 citation statements)

References 48 publications

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“…This was followed by b-cell failure and hyperglycemia in older mice (3). We also found how the first phase in bTsc2 2/2 mice is characterized by both an increase of mitochondrial mass and enhanced glucose-stimulated insulin secretion (12). Autophagy is a cytoprotective mechanism also found essential for b-cell homeostasis (13,14).…”

mentioning

confidence: 54%

“…Tsc2 flox/flox were used as control mice. Animals were maintained as described before (3,12). For rapamycin treatment, bTsc2…”

Section: Btsc2mentioning

confidence: 99%

“…Pancreatic islets were isolated by collagenase digestion of exocrine pancreas and Histopaque density-gradient centrifugation as previously described (3,10,12). Isolated islets were cultured overnight in RPMI1640 supplemented with 10% FBS and antibiotics.…”

Section: Islet Isolation and Immunostainingmentioning

confidence: 99%

“…Pancreatic tissue was obtained from two mice per age and genotype and processed as previously described (12). Thin sections (60-70 nm) were obtained with an Ultracut E (Leica) ultramicrotome, stained with lead citrate, and examined under a JEM-1010 transmission electron microscope (JEOL).…”

Section: Electron Microscopy and Immunogold Labelingmentioning

confidence: 99%

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Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

et al. 2014

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Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in b-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in b-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with b-cell-specific deletion of Tsc2 (bTsc2 2/2 ) and, consequently, mTORC1 hyperactivation, we focused on the role that chronic mTORC1 hyperactivation might have on b-cell failure. mTORC1 hyperactivation drove an early increase in b-cell mass that later declined, triggering hyperglycemia. Apoptosis and endoplasmic reticulum stress markers were found in islets of older bTsc2 2/2 mice as well as accumulation of p62/SQSTM1 and an impaired autophagic response. Mitochondrial mass was increased in b-cells of bTsc2 2/2 mice, but mitophagy was also impaired under these circumstances. We provide evidence of b-cell autophagy impairment as a link between mTORC1 hyperactivation and mitochondrial dysfunction that probably contributes to b-cell failure.Nutrient overload is one of the main causes of insulin resistance. This triggers the compensatory mechanisms leading to b-cell mass increase and hyperinsulinemia. Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) is elicited under nutrient overload conditions (1-3). mTORC1 plays a positive role in b-cell mass expansion (3-6), and rapamycin treatment impairs b-cell mass adaptation (7,8). On the other hand, mTORC1 hyperactivation is also a cause of insulin resistance (1) and endoplasmic reticulum (ER) stress (9), conditions linked with b-cell dysfunction and diabetes progression (10,11). We previously described how Tsc2 deletion in b-cells (bTsc2 2/2 ) results in chronic mTORC1 hyperactivation leading to a biphasic phenotype with early b-cell mass increase, hyperinsulinemia, and hypoglycemia. This was followed by b-cell failure and hyperglycemia in older mice (3). We also found how the first phase in bTsc2 2/2 mice is characterized by both an increase of mitochondrial mass and enhanced glucose-stimulated insulin secretion (12). Autophagy is a cytoprotective mechanism also found essential for b-cell homeostasis (13,14). Autophagy plays a protective role under stress conditions, such as ER stress (15), and we and others have described its positive role in b-cells under these conditions (16,17). Autophagy is also responsible for the turnover of mitochondria by the specific elimination of defective or damaged organelles. mTORC1 is a critical negative regulator of autophagy (18), and studies have shown how TSC deficiency leads to impaired autophagy in human tumors and cell lines (19,20). In this study, we explored the intriguing possibility that mTORC1 hyperactivity in b-cells, apart from being essential for b-cell compensatory mechanisms, might

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confidence: 54%

“…Tsc2 flox/flox were used as control mice. Animals were maintained as described before (3,12). For rapamycin treatment, bTsc2…”

Section: Btsc2mentioning

confidence: 99%

Section: Islet Isolation and Immunostainingmentioning

confidence: 99%

Section: Electron Microscopy and Immunogold Labelingmentioning

confidence: 99%

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Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

et al. 2014

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“…For instance, mTORC1 activation increases the number of copies of mitochondrial DNA and the expression of genes that encode proteins regulating mitochondrial metabolism (Cunningham et al, 2007;Koyanagi et al, 2011). Consequently, the genetic ablation of mTORC1 in mouse heart or skeletal muscle reduces the number of mitochondria and the expression of oxidative genes (Bentzinger et al, 2008;Romanino et al, 2011;Shende et al, 2011).…”

Section: Mtorc1 Regulates Ppara Activity and Hepatic Ketogenesismentioning

confidence: 99%

Regulation of mTORC1 and its impact on gene expression at a glance

Laplante

Sabatini

2013

Journal of Cell Science

541

533

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The mechanistic (or mammalian) target of rapamycin (mTOR) is a kinase that regulates key cellular functions linked to the promotion of cell growth and metabolism. This kinase, which is part of two protein complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2), has a fundamental role in coordinating anabolic and catabolic processes in response to growth factors and nutrients. Of the two mTOR complexes, mTORC1 is by far the best characterized. When active, mTORC1 triggers cell growth and proliferation by promoting protein synthesis, lipid biogenesis, and metabolism, and by reducing autophagy. The fact that mTORC1 deregulation is associated with several human diseases, such as type 2 diabetes, cancer, obesity and neurodegeneration, highlights its importance in the maintenance of cellular homeostasis. Over the last years, several groups observed that mTORC1 inhibition, in addition to reducing protein synthesis, deeply affects gene transcription. Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARγ, PPARα, HIF1α, YY1–PGC1α and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts.

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Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency‐mediated mitochondrial dysregulation

Whang

Kim

Cho

et al. 2018

Journal Cellular Physiology

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Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has significant potential for application in the treatment of urothelial carcinoma (URCa) of the bladder. Previous studies have shown that regulation of the AMP‐activated serine/threonine protein kinase (AMPK)–mTOR signaling pathway enhances apoptosis by inducing autophagy or mitophagy in bladder cancer. Alteration of liver kinase B1 (LKB1)‐AMPK signaling leads to mitochondrial dysfunction and the accumulation of autophagy‐related proteins as a result of mitophagy, resulting in enhanced cell sensitivity to drug treatments. Therefore, we hypothesized that LKB1 deficiency in URCa cells could lead to increased sensitivity to rapamycin by inducing mitochondrial defect‐mediated mitophagy. To test this, we established stable LKBI‐knockdown URCa cells and analyzed the effects of rapamycin on their growth. Rapamycin enhanced growth inhibition and apoptosis in stable LKB1‐knockdown URCa cells and in a xenograft mouse model. In spite of the stable downregulation of LKB1 expression, rapamycin induced AMPK activation in URCa cells, causing loss of the mitochondrial membrane potential, ATP depletion, and ROS accumulation, indicating an alteration of mitochondrial biogenesis. Our findings suggest that the absence of LKB1 can be targeted to induce dysregulated mitochondrial biogenesis by rapamycin treatment in the design of novel therapeutic strategies for bladder cancer.

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Ablation of TSC2 Enhances Insulin Secretion by Increasing the Number of Mitochondria through Activation of mTORC1

Cited by 53 publications

References 48 publications

Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

Pancreatic β-Cell Failure Mediated by mTORC1 Hyperactivity and Autophagic Impairment

Regulation of mTORC1 and its impact on gene expression at a glance

Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency‐mediated mitochondrial dysregulation

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