Bienvenu(e) sur le site de l'Institut Necker Enfants Malades

Etudier les troubles de croissance et métabolisme dans des maladies rares de l\\\'enfant

de la science fondamentale :
  • croissance
  • métabolisme
à la recherche translationnelle :
  • maladies métaboliques rares et cancer
Mario Pende
Contrôle de la croissance cellulaire par les nutriments
Birthdate and Citizenship: February 11, 1967. Italian and French
Education: Master in Pharmacology, University of Genova, Italy (1993). PhD degree, Biochemistry, Summa cum laude, University of Basel, Switzerland (2000).
Professional experience: Visiting Scientist, NICHD, NIH, Bethesda, Maryland, US (1993-1996). PhD student supervised by G. Thomas, Friedrich Miescher Inst., Basel, Switzerland (1996-2000). Post-doctoral Scientist, Friedrich Miescher Inst., Basel, Switzerland (2000-2001). Principal Investigator, Avenir Program, INSERM, Necker Institute, Paris, France (2002). Tenured, INSERM (2007).
Awards: Morgagni Prize for Studies on Metabolism (2006), Schlumberger Foundation Award (2006), ERC European Research Council Awards- Starting and Consolidator grants (2008 and 2013), Prix de l’Académie des Sciences-Biologie integrative (2014), Visiting professor, Nankai University, Tianjin, China (2016)


In metazoans, nutrient and growth factor availability control cell number, size and metabolic homeostasis. We investigate the specific programs underlying these responses, and their coordination by signal transduction mechanisms.


We focus on two nutrient signal transduction pathways, the mTOR (mammalian Target Of Rapamycin) and the Vps15/Vps34 complex (Vacuolar Protein Sorting15/34). These ancient pathways are present in every eukaryotic cell, from unicellular organisms like yeast to humans. They function as essential mechanisms that direct how growth and metabolism adapt to nutritional cues. mTOR is a Ser/Thr protein kinase, while the Vps15/Vps34 complex is a lipid kinase with phosphatidylinositol 3-kinase activity (class III PI3K). The transduction mechanisms triggered by mTOR and class III PI3K are complex. In mammalian cells, both kinases are engaged in multiple complexes that have different localization, targets and sensitivities to upstream signals, like nutrients and insulin.

We have contributed to demonstrate that this crosstalk and differential regulation may explain many physiological responses to nutrition. For instance, why nutrients and insulin are synergistic for cell growth, though nutrients cause resistance to the metabolic action of insulin. Or why insulin inhibits autophagy, though stimulates receptor trafficking. During the past fifteen years we have generated and characterized a wide panel of mouse mutants in the mTOR and class III PI3K pathways. We were involved in revealing unique and interesting phenotypes that increased our knowledge of mTOR/class III PI3K roles in pathophysiology: mutants with small cells (Pende et al., Nature, 2000; Ohanna et al., Nature Cell Biol, 2005), mutants resistant to tumorigenesis in specific tissues and after specific oncogenic insults (Alliouachene et al., JCI, 2008; Panasyuk et al., Nature Comm., 2012; Patitucci et al., JCI, 2017), mutants with muscle disease (Risson et al., JCB, 2009; Nemazanyy et al., EMBO Mol Med, 2013), mutants mimicking caloric restriction and promoting longevity (Aguilar et al., Cell Metabolism, 2007; Barilari et al., EMBO J, 2017), mutants with altered insulin action (Nemazanyy et al., Nature Comm., 2015; Treins et al., Mol Cel Biol, 2012).

Research objectives

The scientific questions posed by our group are:

  1. How are controlled fundamental processes including cell size control and organismal longevity? To this end, we want to determine the molecular targets of the nutrient-activated mTORC1/S6 kinase cassette that may explain the alterations in cell size and lifespan when these kinases are deregulated.
  2. What human genetic diseases arise from pathological changes in the activities of the mTOR or may benefit from therapeutical intervention on these pathways? These diseases include Tuberous Sclerosis Complex (TSC) and other mTORopathies, in patient healthcare at the Necker Children Hospital.
  3. How are the pathological changes in neural differentiation, neuronal excitability, cyst formation triggered by aberrant mTOR activation?

5 main recent publications

  • Bonucci M., et al (2020). S6K1-dependent polycystic kidney in Tuberous Sclerosis disconnects the controls of cell division rate and orientation by mTOR. Nature Communications, 11(1):3200.
  • Rashid T., et al (2018). Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. EMBO J, 38(1):e99576
  • Patitucci C, et al. (2017) HNF1α suppresses steatosis associated liver cancer by inhibiting PPARγ transcription. The Journal of clinical investigation, 127, 1873-1888.
  • Barilari M, et al. (2017) ZRF1 is a novel S6 kinase substrate that drives the senescence program. The EMBO journal, 36, 736-750.
  • Liang N, et al. (2014) Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. The Journal of experimental medicine 211(11):2249-2263.
30 dernières publications


  • de la Calle Arregui C., Plata-Gomez A.B., Deleyto-Seldas N., Garcia F., Ortega-Molina A., Abril-Garrido J., Rodriguez E., Nemazanyy I., Tribouillard L., de Martino A., Caleiras E., Campos-Olivas R., Mulero F., Laplante M., Muñoz J., Pende M., Sabio G., Sabatini D.M., Efeyan A. (2021). Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling. Nat. Comm, 12(1):3660. doi: 10.1038/s41467-021-23857-8.
  • 2020

  • Bonucci M., Kuperwasser N., Barbe S., Koka V., de Villeneuve D., Zhang C., Srivastava N., Jia X., Stokes M.P., Bienaimé F., Verkarre V., Lopez J.B., Jaulin F., Pontoglio M., Terzi F., Delaval B., Piel M., Pende M. (2020). S6K1-dependent polycystic kidney in Tuberous Sclerosis disconnects the controls of cell division rate and orientation by mTOR. Nat. Comm, 11(1):3200. doi: 10.1038/s41467-020-16978-z.
  • 2019

  • Murakami S., Nemazanyy I., White S.M., Chen H., Nguyen C.D.K., Graham G.T., Saur D., Pende M., Yi C. (2019). A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas. Dev Cell, doi: 10.1016/j.devcel.2019.07.022.
  • White S.M., Avantaggiati M.L., Nemazanyy I., Di Poto C., Yang Y., Pende M., Gibney G.T., Ressom H.W., Field J., Atkins M.B., Yi C. (2019). YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells. Dev Cell, 49, 425-443.
  • Iershov A., Nemazanyy I., Alkhoury C., Girard M., Barth E., Cagnard N., Montagner A., Chretien D., Rugarli E.I., Guillou H., Pende M., Panasyuk G. (2019). The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα. Nat Comm., 10, 1566.
  • Thery M., Pende M. (2019). Golgi mechanics controls lipid metabolism. Nat. Cell. Biol.
  • 2018

  • Rashid T., Nemazanyy I., Paolini C., Tatsuta T., Crespin P., de Villeneuve D., Brodesser S., Benit P., Rustin P., Baraibar M.A., Agbulut O., Olivier A., Protasi F., Langer T., Chrast R., de Lonlay P., de Foucauld H., Blaauw B., Pende M. (2018). Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. EMBO J, 38.
  • 2017

  • Patitucci C., Couchy G., Bagattin A., Cañeque T., de Reyniès A., Scoazec J-Y, Rodriguez R., Pontoglio M., Zucman-Rossi J., Pende M.* and Panasyuk G. (2017) *corresponding author. HNF1α suppresses steatosis associated liver cancer by inhibiting PPARγ transcription. Journal of Clinical Investigation, 127, 1873-1888, doi: 10.1172/JCI90327.
  • Barilari M., Bonfils G., Treins C., Koka V., De Villeneuve D., Fagrega S., Pende M. (2017) ZRF1 is a novel S6 kinase substrate that drives the senescence program. EMBO J., 36, 736-750. doi: 10.15252/embj.201694966.
  • Panasyuk G, Patitucci C, Espeillac C, Pende M. The role of the mTOR pathway during liver regeneration and tumorigenesis. Ann Endocrinol (Paris). 2013;74(2):121-2. PMID: 23566619
  • Patitucci C, Couchy G, Bagattin A, Cañeque T, de Reyniès A, Scoazec JY, Rodriguez R, Pontoglio M, Zucman-Rossi J, Pende M, Panasyuk G. Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription. J Clin Invest. 2017;127(5):1873-1888. PMID: 28394260
  • Barilari M, Bonfils G, Treins C, Koka V, De Villeneuve D, Fabrega S, Pende M. ZRF1 is a novel S6 kinase substrate that drives the senescence programme. EMBO J. 2017 Feb 27. pii: e201694966. doi: 10.15252/embj.201694966. [Epub ahead of print]
  • 2016

  • Marabita M, Baraldo M, Solagna F, Ceelen JJ, Sartori R, Nolte H, Nemazanyy I, Pyronnet S, Kruger M, Pende M, Blaauw B. S6K1 Is Required for Increasing Skeletal Muscle Force during Hypertrophy. Cell Rep. 2016 Oct 4;17(2):501-513.
  • Sahin M, Henske EP, Manning BD, Ess KC, Bissler JJ, Klann E, Kwiatkowski DJ, Roberds SL, Silva AJ, Hillaire-Clarke CS, Young LR, Zervas M, Mamounas LA; Tuberous Sclerosis Complex Working Group to Update the Research Plan. Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference. Pediatr Neurol. 2016 Jul;60:1-12.
  • Houssaini A, Abid S, Derumeaux G, Wan F, Parpaleix A, Rideau D, Marcos E, Kebe K, Czibik G, Sawaki D, Treins C, Dubois-Randé JL, Li Z, Amsellem V, Lipskaia L, Pende M, Adnot S. Selective TSC1 Deletion in Smooth Muscle Activates mTOR Signaling and Induces Pulmonary Hypertension. Am J Respir Cell Mol Biol. 2016 Sep;55(3):352-67.
  • Marsan E, Ishida S, Schramm A, Weckhuysen S, Muraca G, Lecas S, Liang N, Treins C, Pende M, Roussel D, Le Van Quyen M, Mashimo T, Kaneko T, Yamamoto T, Sakuma T, Mahon S, Miles R, Leguern E, Charpier S, Baulac S. Depdc5 knockout rat: A novel model of mTORopathy. Neurobiol Dis. 2016 May;89:180-9.
  • Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, and al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016 Jan 2;12(1):1-222. No abstract available.
  • 2015

  • Liang N, Pende M. YAP enters the mTOR pathway to promote tuberous sclerosis complex. Mol Cell Oncol. 2015 May 1;2(4):e998100. doi: 10.1080/23723556.2014.998100. eCollection 2015 Oct-Dec.
  • Nemazanyy I, Montagnac G, Russell RC, Morzyglod L, Burnol AF, Guan KL, Pende M, Panasyuk G. Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling. Nat Commun. 2015 Sep 21;6:8283. doi: 10.1038/ncomms9283.
  • Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, Jones C, Radulescu S, Huels DJ, Myant KB, Dudek KM, Casey HA, Scopelliti A, Cordero JB, Vidal M, Pende M, Ryazanov AG, Sonenberg N, Meyuhas O, Hall MN, Bushell M, Willis, AE, Sansom OJ. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2015 Jan 22;517(7535):497-500.
  • 2014

  • Liang N, Zhang C, Dill P, Panasyuk G, Pion D, Koka V, Gallazzini M, Olson EN, Lam H, Henske EP, Dong Z, Apte U, Pallet N, Johnson RL, Terzi F, Kwiatkowski DJ, Scoazec JY, Martignoni G, Pende M. Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J Exp Med. 2014 Oct 20;211(11):2249-63.
  • Chauvin C, Koka V, Nouschi A, Mieulet V, Hoareau-Aveilla C, Dreazen A, Cagnard N, Carpentier W, Kiss T, Meyuhas O, Pende M. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene. 2014 Jan 23;33(4):474-83.
  • 2013

  • Canaud G, Bienaimé F, Viau A, Treins C, Baron W, Nguyen C, Burtin M, Berissi S, Giannakakis K, Muda AO, Zschiedrich S, Huber TB, Friedlander G, Legendre C, Pontoglio M, Pende M, Terzi F. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med. 2013 Oct;19(10):1288-96.
  • Michot C, Mamoune A, Vamecq J, Viou MT, Hsieh LS, Testet E, Lainé J, Hubert L, Dessein AF, Fontaine M, Ottolenghi C, Fouillen L, Nadra K, Blanc E, Bastin J, Candon S, Pende M, Munnich A, Smahi A, Djouadi F, Carman GM, Romero N, de Keyzer Y, de Lonlay P. Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts. Biochim Biophys Acta. 2013 Dec;1832(12):2103-14.
  • Nemazanyy I, Espeillac C, Pende M, Panasyuk G. Role of PI3K, mTOR and Akt2signalling in hepatic tumorigenesis via the control of PKM2 expression. Biochem Soc Trans. 2013 Aug;41(4):917-22.
  • Nemazanyy I, Blaauw B, Paolini C, Caillaud C, Protasi F, Mueller A, Proikas-Cezanne T, Russell RC, Guan KL, Nishino I, Sandri M, Pende M, Panasyuk G. Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease. EMBO Mol Med. 2013 Jun;5(6):870-90.
  • Panasyuk G, Patitucci C, Espeillac C, Pende M. The role of the mTOR pathway during liver regeneration and tumorigenesis. Ann Endocrinol (Paris). 2013 May;74(2):121-2.
  • 2012

  • Nadra K, Médard JJ, Mul JD, Han GS, Grès S, Pende M, Metzger D, Chambon P, Cuppen E, Saulnier-Blache JS, Carman GM, Desvergne B, Chrast R. Cell autonomous lipin 1 function is essential for development and maintenance of white and brown adipose tissue. Mol Cell Biol. 2012 Dec;32(23):4794-810.
  • Treins C, Alliouachene S, Hassouna R, Xie Y, Birnbaum MJ, Pende M. The combined deletion of S6K1 and Akt2 deteriorates glycemic control in a high-fat diet. Mol Cell Biol. 2012 Oct;32(19):4001-11.
  • Panasyuk G, Espeillac C, Chauvin C, Pradelli LA, Horie Y, Suzuki A, Annicotte JS, Fajas L, Foretz M, Verdeguer F, Pontoglio M, Ferré P, Scoazec JY, Birnbaum MJ, Ricci JE, Pende M. PPARγ contributes to PKM2 and HK2 expression in fatty liver. Nat Commun. 2012 Feb 14;3:672.
  • Kalista S, Schakman O, Gilson H, Lause P, Demeulder B, Bertrand L, Pende M, Thissen JP. The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy. Endocrinology. 2012 Jan;153(1):241-53.
  • Chercheur statutaire
    Stefano Fumagalli
    +33 (0)1 40 61 53 41
    Lida Katsimpardi
    Mario Pende
    +33 (0)1 40 61 53 43
    ITA statutaire
    Delphine De Villeneuve
    Ingénieur(e) en techniques biologiques
    +33 (0)1 40 61 53 42
    Vonda Koka
    Ingénieur(e) en techniques biologiques
    +33 (0)1 40 61 53 39
    Orestes Lopez Ortega
    Soumia Abdellaoui
    Francesco Avanzi
    Alexia Bankole
    +33 (0)1 40 61 53 42
    Khaled Tighanimine
    Javier Carrasco
    Master 2

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    S.A.R. la Princesse Caroline de Hanovre qui, à travers la Fondation Princesse Grace, soutient déjà la recherche medicale et tout ce qui contribue à soulager les enfants malades en France et dans le monde, a accepté de s'engager à nos cotés pour que ce centre de medecine moleculaire, tourné entre autres vers les pathologies des enfants, prenne de vitesse les maladies et continue à relever les defis actuels.

    INEM - Organigramme