mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway

Peterson, Timothy R.; Sengupta, Shomit; Harris, Thurl E.; Carmack, Anne E.; Kang, Seong A.; Balderas, Eric; Guertin, David A.; Madden, Katherine L.; Carpenter, Anne E.; Finck, Brian N.; Sabatini, David M.

doi:10.1016/j.cell.2011.06.034

Cited by 1,028 publications

(1,016 citation statements)

References 73 publications

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“…In addition, mTORC1 was shown to modulate the actions of mature SREBPs by regulating the localization of lipin‐1. When mTORC1 is suppressed, lipin‐1 translocates to the nucleus and inhibits nuclear accumulation of SREBP1 and SREBP2 (Peterson et al, 2011). …”

Section: Mtor and Metabolismmentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

133

120

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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Section: Mtor and Metabolismmentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

133

120

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“…For example, mTORC1 also controls growth by negatively regulating autophagy through the direct phosphorylation of Unc-51-like kinase (ULK1; discussed below) (Chan 2009;Ganley et al 2009;Hosokawa et al 2009;Jung et al 2009). In addition, mTORC1 directly phosphorylates the phosphatidate phosphatase Lipin1 (which regulates lipid metabolism through SREBP1) and the growth factor receptor-bound protein 10 (Grb10; part of a negative feedback loop targeting insulin receptor signaling) (Hsu et al 2011;Peterson et al 2011;Yu et al 2011). In fact, two recent proteomic studies identifying Grb10 as an mTORC1 substrate further suggest that the insulin-stimulated phosphorylation cascade is largely mTOR-dependent (Hsu et al 2011;Yu et al 2011).…”

Section: The Mtor Complexes and Their Regulationmentioning

confidence: 99%

mTOR-Dependent Cell Survival Mechanisms

Hung

García-Haro

Sparks

et al. 2012

Cold Spring Harbor Perspectives in Biology

163

135

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The mechanistic target of rapamycin (mTOR) kinase is a conserved regulator of cell growth, proliferation, and survival. In cells, mTOR is the catalytic subunit of two complexes called mTORC1 and mTORC2, which have distinct upstream regulatory signals and downstream substrates. mTORC1 directly senses cellular nutrient availability while indirectly sensing circulating nutrients through growth factor signaling pathways. Cellular stresses that restrict growth also impinge on mTORC1 activity. mTORC2 is less well understood and appears only to sense growth factors. As an integrator of diverse growth regulatory signals, mTOR evolved to be a central signaling hub for controlling cellular metabolism and energy homoeostasis, and defects in mTOR signaling are important in the pathologies of cancer, diabetes, and aging. Here we discuss mechanisms by which each mTOR complex might regulate cell survival in response to metabolic and other stresses.

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“…Studies indicate that mTORC1, which is activated by growth factors and amino acids, is a key sensor allowing cells and tissues to adapt their metabolism in response to the nutritional state (5). In the liver, it controls the activation of various metabolic processes including lipogenesis (6) and ketogenesis (3). Recent observations indicate that mTORC1 regulates mitochondrial biogenesis and metabolism (7,8), but the underlying mechanisms remain to be determined.…”

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confidence: 99%

A Mitofusin-2–dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver

Sood

Jeyaraju

Prudent

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

157

178

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Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30%, and mitochondrial respiratory capacity decreases by 20%. Instead, mitochondria-ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria-ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.T he last decade expanded our understanding of the importance of mitochondrial shape, position, and interorganellar interactions in the regulation of cell stress. For example, mitochondrial hyperfusion is a stress response that protects against cell death and autophagic degradation, whereas chronic stress triggers mitochondrial fragmentation and cell death. However, the in vivo implications of mitochondrial plasticity under normal physiological conditions are still largely unknown. The liver is a key organ responsible for nutrient sensing and the maintenance of wholebody energy homeostasis. Therefore, we considered the liver as a primary model to examine the changes in mitochondrial plasticity that accompanies physiological transitions in feeding and postprandial metabolism (1-4).The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionary conserved serine/threonine kinase that plays an important role in regulating metabolism and cell growth in response to anabolic signals (5). Studies indicate that mTORC1, which is activated by growth factors and amino acids, is a key sensor allowing cells and tissues to adapt their metabolism in response to the nutritional state (5). In the liver, it controls the activation of various metabolic proce...

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mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway

Cited by 1,028 publications

References 73 publications

Myelination and mTOR

Myelination and mTOR

mTOR-Dependent Cell Survival Mechanisms

A Mitofusin-2–dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver

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