Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells

Nakada, Daisuke; Saunders, Thomas L.; Morrison, Sean J.

doi:10.1038/nature09571

Cited by 465 publications

(477 citation statements)

References 45 publications

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“…One major observation in this study is that a physiological trigger of autophagy, such as nutrient deprivation, is able to induce DNA damage through the generation of ROS. Genotoxic stress has been reported to repress mTOR in response to oxidative stress caused by ROS through a cytoplasmic signaling node for LKB1/AMPK/TSC2 activation in response to oxidative stress [31]. The COMET assay and histone γ-H2AX accumulation confirmed the persistence of damaged DNA and the level of initial damage corresponded with the cell's ability to initiate autophagy.…”

Section: Discussionmentioning

confidence: 94%

ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

et al. 2012

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In response to nutrient stress, cells start an autophagy program that can lead to adaptation or death. The mechanisms underlying the signaling from starvation to the initiation of autophagy are not fully understood. In the current study we show that the absence or inactivation of PARP-1 strongly delays starvation-induced autophagy. We have found that DNA damage is an early event of starvation-induced autophagy as measured by γ-H2AX accumulation and comet assay, with PARP-1 knockout cells displaying a reduction in both parameters. During starvation, ROSinduced DNA damage activates PARP-1, leading to ATP depletion (an early event after nutrient deprivation). The absence of PARP-1 blunted AMPK activation and prevented the complete loss of mTOR activity, leading to a delay in autophagy. PARP-1 depletion favors apoptosis in starved cells, suggesting a pro-survival role of autophagy and PARP-1 activation after nutrient deprivation. In vivo results show that neonates of PARP-1 mutant mice subjected to acute starvation, also display deficient liver autophagy, implying a physiological role for PARP-1 in starvation-induced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation.

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Section: Discussionmentioning

confidence: 94%

ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

et al. 2012

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“…This general theme has also been expanded by three recent studies in which the tumor suppressor and metabolic regulator LKB1 was shown to regulate HSC quiescence (51)(52)(53). In the absence of LKB1, stem cells appeared to proliferate initially, giving rise to increased progenitor cell number.…”

Section: Energy Metabolism Mitochondria and Stem Cellsmentioning

confidence: 93%

Signal Transduction by Mitochondrial Oxidants

Finkel

2012

Journal of Biological Chemistry

353

252

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The production of mitochondrial reactive oxygen species occurs as a consequence of aerobic metabolism. Mitochondrial oxidants are increasingly viewed less as byproducts of metabolism and more as important signaling molecules. Here, I review several notable examples, including the cellular response to hypoxia, aspects of innate immunity, the regulation of autophagy, and stem cell self-renewal capacity, where evidence suggests an important regulatory role for mitochondrial oxidants.Mitochondria are believed to be the major source of intracellular reactive oxygen species (ROS) 2 generation. Working with isolated mitochondria, some estimates have suggested that as much as 3-5% of the oxygen consumed is ultimately diverted toward ROS production (1). Although these estimates are potential benchmarks, the experimental conditions, including substrate concentration and ATP levels, in which many of these measurements were made, as well as the functional alterations that occur with mitochondrial isolation, argue for caution with regard to such in vitro determinations. As such, the precise in vivo amount of mitochondrial superoxide or hydrogen peroxide production remains elusive. Although the magnitude of ROS production remains in doubt, the location of the one-electron reduction of molecular oxygen is less uncertain. Both Complexes I and III of the electron transport chain are thought to be the major sites of ROS production (2, 3), although clearly other electron complexes, as well as other mitochondrial enzymes, can generate ROS. Once generated, superoxide rapidly and spontaneously dismutates to hydrogen peroxide. This conversion is accelerated in the presence of the enzyme superoxide dismutase. To avoid the potential damaging effects of ROS, mitochondria express a number of protein antioxidants, including SOD2, as well as other scavenging enzymes such as peroxiredoxins 3 and 5. Although the activities of intracellular antioxidants and peroxidases determine the magnitude of ROS, the level of ROS generated is also believed to be dependent on certain intrinsic properties of mitochondrial energetics. For instance, a high proton motive force (e.g. high m ) is believed to favor the production of ROS, whereas mitochondrial uncoupling agents result in a lower m and decreased ROS formation. Similarly, mutations in either mitochondrial DNA or nuclear DNA that lead to disruption in any of the components of the electron transport chain also predispose to ROS formation presumably by impeding the flow of electrons down the cytochrome chain.Although the regulation of mitochondrial ROS release was experimentally appreciated, for many years, the prevailing view was that mitochondrial oxidants were autonomously produced solely as a byproduct of metabolism. That notion has slowly given way to a more nuanced view of mitochondrial oxidants as potential regulators of a number of intracellular pathways. Initial reports suggested that increased supply of metabolic substrates augmented mitochondrial oxidant production and that the release of o...

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“…However, targeting liver kinase B1 (LKB1) in the beta cell for the treatment of diabetes would be undesirable as knockout of Lkb1 in adult mice has a deleterious effect on haematopoietic stem cell maturation [20][21][22]. We and others have identified non-overlapping functions in beta cells for LKB1 targets, including MAP/microtubule affinityregulating kinase 2 (MARK2), salt-inducible kinase 2 (SIK2), brain-specific kinase 2 (BRSK2) as well as AMPactivated protein kinase (AMPK) itself [19,[23][24][25][26][27][28], underscoring the potential for identifying the minimal target(s) of LKB1 responsible for enhancing insulin secretion.…”

Section: Introductionmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

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Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

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Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells

Cited by 465 publications

References 45 publications

ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

Signal Transduction by Mitochondrial Oxidants

LKB1 couples glucose metabolism to insulin secretion in mice

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