mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation

Morita, Masahiro; Gravel, Simon-Pierre; Chénard, Valérie; Sikström, Kristina; Zheng, Liang; Alain, Tommy; Gandin, Valentina; Avizonis, Daina; Arguello, Meztli; Zakaria, Chadi; McLaughlan, Shannon; Nouët, Yann; Pause, Arnim; Pollak, Michael; Gottlieb, Eyal; Larsson, Ola; St-Pierre, Julie; Topisirović, Ivan; Sonenberg, Nahum

doi:10.1016/j.cmet.2013.10.001

Cited by 705 publications

(693 citation statements)

References 67 publications

(101 reference statements)

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“…Conversely, a substantial impairment of mitophagy was consistently observed (Korolchuk et al, 2017). While mTOR is clearly involved in the regulation of mitochondrial homeostasis and mitochondrial biogenesis (Morita et al, 2013), its regulatory role in mitophagy has been underestimated. Here, we provide evidence that rapamycin, an inhibitor of the mTORC1 complex, completely restores mitophagy and prevents all the features associated with mitochondrial dysfunction, DDR and senescence.…”

Section: Discussionmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H2O2 derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21cip, p16ink4a, and p15ink4b and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies.

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Section: Discussionmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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“…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.It has been established that the core machinery that governs mitochondrial shape and ultrastructure is essential. Indeed, genetic ablation of its components, which includes the outer mitochondrial membrane (OMM) fusion GTPase Mitofusin-1 (Mfn1) and Mfn2 (9) as well as the inner mitochondrial membrane (IMM) GTPase Optic atrophy 1 (Opa1) (10), is embryonic lethal.…”

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confidence: 99%

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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.

162

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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“…First, that mitochondrial ATP production is limiting, particularly under high growth conditions, suggesting further that rapidly growing cells operate under an ATP deficit. Protein synthesis requires a large expenditure of ATP; the observation that Tor induces mitochondrial protein translation to increase ATP production is consistent with this view (Morita et al ., 2013). Second, that mitophagy decreases ATP production, at least in the short term; mitophagy requires several hours, and during this time, the engulfed mitochondrion is not able to contribute to ATP production.…”

Section: Iis Inhibits Mitochondrial Quality Control By Inhibiting Mitmentioning

confidence: 99%

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

Stern

2017

Aging Cell

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SummaryThe antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin‐regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term. I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial ROS generation, which signals inhibition of mitophagy via ROS‐dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

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mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation

Cited by 705 publications

References 67 publications

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

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

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

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