Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Chae, Young Chan; Vaira, Valentina; Caino, M. Cecilia; Tang, Hsin‐Yao; Seo, Jae Ho; Kossenkov, Andrew V.; Ottobrini, Luisa; Martelli, Cristina; Lucignani, Giovanni; Bertolini, Irene; Locatelli, Marco; Bryant, Kelly G.; Ghosh, Jagadish C.; Lisanti, Sofia; Ku, Bonsu; Bòsari, Silvano; Languino, Lucia R.; Speicher, David W.; Altieri, Dario C.

doi:10.1016/j.ccell.2016.07.004

Cited by 170 publications

(164 citation statements)

References 45 publications

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“…Simulation of a cell with IGF-1 or heat shock stress, induced translocation of AKT to the mitochondria within only several minutes after the stimulation, and the mitochondrial AKT was in its phosphorylated and activated form [22]. Young, et al, a study which profiled the mitochondrial phosphoproteome of prostate adenocarcinoma PC3 cells exposed to severe hypoxia found that active AKT accumulates in the mitochondria under hypoxia [23]. When Mitochondrial ATP-sensitive potassium channel (mitoKATP), a common effector of protective stimuli in myocardial ischemia-reperfusion injury (MIRI), opens it plays a physiologic role in triggering cardiomyocytes' energy homeostasis during MIRI [15].…”

Section: Discussionmentioning

confidence: 99%

PI3K–AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT

Song

Chu

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The phosphatidylinositol-3-kinase -AKT (PI3K-AKT) is an important intracellular signal pathway in regulating cell proliferation, differentiation and apoptosis. In previous studies, we’ve demonstrated that PI3K–AKT pathway protects cardiomyocytes from ischemic and hypoxic apoptosis through mitochondrial function. However, the molecular mechanisms underlying hypoxia-induced cardiomyocyte apoptosis via PI3K-AKT pathway remain ill-defined. Here, we addressed this question. Methods: Cardiomyocytes were exposed to hypoxia, with/without different inhibitors and then protein levels were assessed by Western blotting. Results: We found that the PI3K–AKT pathway was activated in cardiomyocytes that were exposed to hypoxia. Moreover, the phospho-AKT (pAKT) translocated from cytosol to mitochondria via mitochondrial adenosine triphosphate-dependent potassium (mitoKATP), leading to an increase in cytochrome c oxidase (CcO) activity to suppress apoptosis. On the other hand, the mitoKATP specific blocker, 5-hydroxydecanote (5-HD), or suppression of CcO using siRNA, inhibited the pAKT mitochondrial translocation to maintain the CcO activity, resulting in mitochondrial dysfunction and cellular apoptosis induced by hypoxia. Conclusion: These findings suggest that the anti-apoptotic effect of the PI3K-AKT pathway through pAKT translocation to mitochondrial via mitoKATP may be conducted through modification of CcO activity.

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Section: Discussionmentioning

confidence: 99%

PI3K–AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT

Song

Chu

Zhang

et al. 2018

Cell Physiol Biochem

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“…Hypoxia induced AKT accumulation in mitochondria, and phosphorylation of PDK1 has recently been demonstrated to be an additional control mechanism in hypoxic tumour cell metabolism (Chae et al . ). Exacerbated glycolysis leads to accumulation of lactate that must be dealt with to ensure continued cellular function, which led to an interest in understanding the role of monocarboxylate (MCT) lactate/H + membrane symporters in tumour cells (Fig.…”

Section: General Introductionmentioning

confidence: 97%

Hypoxia and cellular metabolism in tumour pathophysiology

Parks

Cormerais

Pouysségur

2017

The Journal of Physiology

118

104

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Adaptation and expansion Developing Tumour Demand SupplyProduction Clearance N u t r i e n t s / e n e r g y M e t a b o l i c w a s t e Hypoxia Abstract Cancer cells are optimised for growth and survival via an ability to outcompete normal cells in their microenvironment. Many of these advantageous cellular adaptations are promoted Scott Parks' work has focused on cellular membrane-transport physiology, first during his PhD at the University of Alberta on aquatic organisms with Dr Greg Goss, followed by transitioning to France to work with Dr Jacques Pouysségur on hypoxia and tumour cell metabolism initially at the University of Nice and now at the Centre Scientifique de Monaco. Yann Cormerais has recently completed his PhD in the Pouysségur lab in Monaco where he has become an expert in tumour amino-acid control pathways and mTOR signalling. Jacques Pouysségur obtained his PhD in 1972 on bacterial genetics at the University of Lyon followed by a two year postdoc at the National Cancer Institute of the NIH. He established his research group in 1978 at the CNRS Biochemistry Centre of the University of Nice. After directing the CNRS ISDBC institute (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008), his team joined the IRCAN institute in Nice and the Centre Scientifique de Monaco. His research has spanned the areas of bacterial and somatic cell genetics, Na + /H + exchange, pH regulation, G protein-coupled receptors and MAP kinase signalling in the context of growth control in mammalian cells. His group has been interested for the last 15 years in hypoxia signalling, angiogenesis, cancer metabolism, nutrient sensing and amino-acid transport.This review was presented at the symposium "Physiological gases in health and disease", which took place at Physiology 2016, Dublin, Ireland, 29-31 July 2016. by the pathophysiological hypoxia that arises in solid tumours due to incomplete vascularisation. Tumour cells are thus faced with the challenge of an increased need for nutrients to support the drive for proliferation in the face of a diminished extracellular supply. Among the many modifications occurring in tumour cells, hypoxia inducible factors (HIFs) act as essential drivers of key pro-survival pathways via the promotion of numerous membrane and cytosolic proteins.Here we focus our attention on two areas: the role of amino acid uptake and the handling of metabolic acid (CO 2 /H + ) production. We provide evidence for a number of hypoxia-induced proteins that promote cellular anabolism and regulation of metabolic acid-base levels in tumour cells including amino-acid transporters (LAT1), monocarboxylate transporters, and acid-base regulating carbonic anhydrases (CAs) and bicarbonate transporters (NBCs). Emphasis is placed on current work manipulating multiple CA isoforms and NBCs, which is at an interesting crossroads of gas physiology as they are regulated by hypoxia to contribute to the cellular handling of CO 2 and pH i regulation. Our research combined with others indicates that targeting of ...

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“…Akt signaling regulates cellular energy metabolism and apoptosis via mechanisms that converge on mitochondria (Stiles, 2009), via its association with HK2 and VDAC (Gottlob et al, 2001), or via the phosphorylation of key proteins, such as BAD (Datta et al, 1997). In addition, Akt acts inside mitochondria, where it can phosphorylate compartment-specific substrates, including the previously cited CypD (Ghosh et al, 2015) and PDK1 (Chae et al, 2016). The intra-mitochondrial Akt activity contributes to apoptosis resistance and tumor growth and might provide a novel adaptive mechanism for tumor resistance to PI3K-based therapy (Ghosh et al, 2015).…”

mentioning

confidence: 99%

Akt‐mediated phosphorylation of MICU 1 regulates mitochondrial Ca ²⁺ levels and tumor growth

et al. 2018

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Although mitochondria play a multifunctional role in cancer progression and Ca2+ signaling is remodeled in a wide variety of tumors, the underlying mechanisms that link mitochondrial Ca2+ homeostasis with malignant tumor formation and growth remain elusive. Here, we show that phosphorylation at the N‐terminal region of the mitochondrial calcium uniporter (MCU) regulatory subunit MICU1 leads to a notable increase in the basal mitochondrial Ca2+ levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion‐targeted Akt strongly regulates the mitochondrial Ca2+ content. The Akt‐mediated phosphorylation impairs MICU1 processing and stability, culminating in reactive oxygen species (ROS) production and tumor progression. Thus, our data reveal the crucial role of the Akt‐MICU1 axis in cancer and underscore the strategic importance of the association between aberrant mitochondrial Ca2+ levels and tumor development.

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Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Cited by 170 publications

References 45 publications

PI3K–AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT

PI3K–AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT

Hypoxia and cellular metabolism in tumour pathophysiology

Akt‐mediated phosphorylation of MICU 1 regulates mitochondrial Ca ²⁺ levels and tumor growth

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Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Cited by 170 publications

References 45 publications

PI3K–AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT

PI3K–AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT

Hypoxia and cellular metabolism in tumour pathophysiology

Akt‐mediated phosphorylation of MICU 1 regulates mitochondrial Ca 2+ levels and tumor growth

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Akt‐mediated phosphorylation of MICU 1 regulates mitochondrial Ca ²⁺ levels and tumor growth