mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology

Betz, Charles; Stracka, Daniele; Prescianotto-Baschong, Cristina; Frieden, Maud; Demaurex, Nicolas; Hall, Michael N.

doi:10.1073/pnas.1302455110

Cited by 464 publications

(462 citation statements)

References 75 publications

(115 reference statements)

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“…Other studies also support that Akt increases mitoHK-II in cardiac and non-cardiac cells. 20,[122][123][124][125][126] PHLPP (PH domain leucine-rich repeat protein phosphatase) is a protein phosphatase 2C family member which has been discovered to dephosphorylate and inhibit Akt. [126][127][128][129][130] Expression of PHLPP is repressed in cancer cells resulting in elevated Akt activation.…”

Section: Akt and Mitochondrial Hk-ii In Protectionmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Akt and Mitochondrial Hk-ii In Protectionmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…53 The PACS genes appeared first in metazoans where they have early-and conserved roles in secretory pathway traffic. 22,23,[54][55][56][57] Sequence alignment and functional analyses reveal that the vertebrate PACS proteins underwent evolutionary adaptation with the acquisition of nuclear-trafficking motifs and, in the case of PACS-2, an Akt phosphorylation site at Ser 437 . 57 The acquisition of nucleartrafficking functions in PACS-2 coincided with the ability of vertebrate p53 to direct cytoprotective p21-dependent cell cycle arrest in addition to its evolutionarily conserved proapoptotic functions.…”

Section: Discussionmentioning

confidence: 99%

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

et al. 2016

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Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2 − / − thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

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“…In liver, the loss of CYPD reduced organelle interactions and induced hepatic insulin resistance, pointing to a new role of MAM integrity in the control of insulin's action [10]. Whereas other studies in mice also suggest a role for MAMs in the control of glucose homeostasis [11][12][13][14], the mechanisms by which disruption of MAMs alters insulin signalling are unknown.…”

Section: Introductionmentioning

confidence: 95%

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

et al. 2015

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Aims/hypothesis Mitochondria-associated endoplasmic reticulum membranes (MAMs) are regions of the endoplasmic reticulum (ER) tethered to mitochondria and controlling calcium (Ca 2+ ) transfer between both organelles through the complex formed between the voltage-dependent anion channel, glucose-regulated protein 75 and inositol 1,4,5-triphosphate receptor (IP3R). We recently identified cyclophilin D (CYPD) as a new partner of this complex and demonstrated a new role for MAMs in the control of insulin's action in the liver. Here, we report on the mechanisms by which disruption of MAM integrity induces hepatic insulin resistance in CypD (also known as Ppif)-knockout (KO) mice. Methods We used either in vitro pharmacological and genetic inhibition of CYPD in HuH7 cells or in vivo loss of CYPD in mice to investigate ER-mitochondria interactions, inter-organelle Ca 2+ exchange, organelle homeostasis and insulin action. Results Pharmacological and genetic inhibition of CYPD concomitantly reduced ER-mitochondria interactions, inhibited inter-organelle Ca 2+ exchange, induced ER stress and altered insulin signalling in HuH7 cells. In addition, histaminestimulated Ca 2+ transfer from ER to mitochondria was blunted in isolated hepatocytes of CypD-KO mice and this was associated with an increase in ER calcium store. Interestingly, disruption of inter-organelle Ca 2+ transfer was associated with ER stress, mitochondrial dysfunction, lipid accumulation, activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)ε and insulin resistance in liver of CypD-KO mice. Finally, CYPD-related alterations of insulin signalling were mediated by activation of PKCε rather than JNK in HuH7 cells. Conclusions/interpretation Disruption of IP3R-mediated Ca 2+ signalling in the liver of CypD-KO mice leads to hepatic insulin resistance through disruption of organelle interaction and function, increase in lipid accumulation and activation of PKCε. Modulation of ER-mitochondria Ca 2+ exchange may thus provide an exciting new avenue for treating hepatic insulin resistance.

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mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology

Cited by 464 publications

References 75 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

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