The role of mitochondrial bioenergetics on the muscular “secretome” during exercise or pathology

Research summary:

I started my research career in Italy, under the supervision of Professors F. Moroni and A. Chiarugi at the School of Medicine of the University of Firenze, Italy. Since the beginning my investigation was focused on understanding how mitochondrial energy metabolism participates in the integration of different cellular functions. In 2009 I moved to Spain where I joined the laboratory of Professor J.M. Cuezva due to his interest in mitochondrial bioenergetics. Nowadays, I am still collaborating with his laboratory investigating the role of mitochondria in cell biology.

Complex regulatory mechanisms enable mitochondrial metabolism to match cell demands, which extend beyond the production of ATP. During the last years we demonstrated that mitochondrial oxidative phosphorylation (OXPHOS) plays further roles in controlling cell death (EMBO J, 2014), immunity (Cell Reports, 2017) and oncogenesis (Mol Cell, 2012). Impaired mitochondrial function deeply alters lipid species and metabolism (Diabetologia, 2017) and is emerging as a pivotal hallmark of pathology. Understanding which products of metabolism are limiting for correct cell function, and how cells obtain or transform them in physiological tissue environments, is crucial to exploit mitochondrial metabolism for therapy.

A main purpose of my research line (now supported by Ramon y Cajal fellowship) is to deepen into the knowledge of mitochondrial metabolism in the pathophysiology of skeletal muscle, the highest oxidative tissue in mammals. Nowadays, we are defining how mitochondria dysfunctions, environmental factors and diet impact metabolism at the cell, tissue, and organism level, and identifying aspects of mitochondria activity that are limiting for cell homeostasis in different contexts. With this purpose we started and strengthened different international collaborations with EU and USA partners and national institutions (CIBERER, i+12 Institute) for translating our understanding of muscle cell metabolism into novel therapy approaches. Ultimately, we aim to provide knowledge based on new mitochondrial aspects for better prevention, diagnosis and therapy of metabolic and rare diseases that have skeletal muscle as a target organ.

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We are defining how skeletal muscle mitochondria dysfunctions act in an autocrine, paracrine and endocrine manner to regulate tissue metabolism. Our final aim is to identify aspects of mitochondria activity that are limiting for whole-body homeostasis in different contexts.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Formentini Laura3264648lformentini(at)cbm.csic.esInvestigador
Herrero MartínJuan Cruz3264648jherrero(at)cbm.csic.esTco. de Investigación y Laboratorio
Sánchez GonzálezCristina3264648Titulado Sup.de Actividades Técn. y Profes. GP1

Relevant publications:

  • Formentini L*, Ryan AJ, Gálvez-Santisteban M, Carter L, Taub P, Lapek JD Jr, Gonzalez DJ, Villarreal F, Ciaraldi TP, Cuezva JM, Henry RR. Mitochondrial H+-ATP synthase in human skeletal muscle: contribution to dyslipidaemia and insulin resistance. Diabetologia. 2017 Oct;60(10):2052-2065 Impact factor: 7.2; (*: corresponding author)
  • Formentini L, Santacatterina F, Núñez de Arenas C, Stamatakis K, López-Martínez D, Logan A, Fresno M, Smits R, Murphy MP, Cuezva JM. Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization. Cell Rep. 2017 May 9;19(6):1202-1213. Impact factor: 8.2
  • Formentini L*, Santacatterina F*, Sánchez-Cenizo L*, Mobasher MA, Casas E, Rueda CB, Martínez-Reyes I, Núñez de Arenas C, García-Bermúdez J, Zapata JM, Sánchez-Aragó M, Satrústegui J, Valverde ÁM, Cuezva JM. Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state. Oncotarget. 2016 Jan 5;7(1):490-508. Impact factor: 6.2(* equally contributed)
  • Formentini L, Pereira MP, Sánchez-Cenizo L, Santacatterina F, Lucas JJ, Navarro C, Martínez-Serrano A and Cuezva JM. In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning. EMBO J. 2014 Apr 1; 33(7):762-78. Impact factor: 12.2
  • Formentini L*, Sánchez-Aragó M*, Martínez-Reyes I, García-Bermudez J, Santacatterina F, Sánchez-Cenizo L, Willers I, Nájera L, Juarránz A, López E, Clofent J, Navarro C, Espinosa E and Cuezva J.M. Regulation and clinical relevance of IF1 in human carcinomas. Oncogenesis 2013 Apr 22;2:e46. Impact Factor: 5 (* equally contributed)
  • Formentini L.*, Sanchez Aragó M*, J.M. Cuezva. Mitochondria-mediated energy adaption in cancer: The H+-ATP synthase-geared switch in human tumors. Antioxidants & Redox Signaling, 2013 Jul 20;19(3):285-98. (* equally contributed). Impact Factor: 8.2.
  • Formentini L, Sanchez Aragó M, Sanchez-Cenizo L, Cuezva J.M. The mitochondrial ATPase Inhibitory Factor 1 (IF1) triggers a ROS-mediated retrograde pro-survival and proliferative response. Mol Cell. 2012 Mar 30;45(6):731-42.  ImpactFactor: 15.4.
  • Pittelli M, Formentini L, Faraco G, Lapucci A, Rapizzi E, Cialdai F, Romano G, Moneti G, Moroni F, Chiarugi A. Inhibition of nicotinamide phosphoribosyl transferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J.Biol.Chem, 2010 Oct 29;285(44):34106-14. ImpactFactor: 5.3.
  • Sánchez-Cenizo L, Formentini L, Aldea M, Ortega A, García-Huerta P, Sánchez-Aragó  M and Cuezva JM. The expression of IF1 inhibits the mitochondrial H+-ATP synthase and mediates the metabolic shift of cells to a Warburg phenotype. J.Biol.Chem, 2010 Aug 13;285(33):25308-13.  ImpactFactor: 5.3.
  • Formentini L, Macchiarulo A, Cipriani G, Camaioni E, Rapizzi E, Pellicciari R, Moroni F, Chiarugi A Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure. J. Biol Chem, 2009 Jun 26;284(26):17668-76. ImpactFactor: 5.3.
  • Formentini L, Moroni F and Chiarugi A. Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo. Biochem Pharmacol, 2009 May 15;77(10):1612-20. ImpactFactor: 4.9
  • Formentini L, Arapitsas P, Pittelli M, Giovannelli, L, Menichetti S, Romani A, Moroni F, Chiarugi A. Mono-galloyl glucose derivatives are potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors and partially reduce PARP-1-dependent cell death. Br J. Pharmacol, 2008 Dec;155(8):1235-49. ImpactFactor: 6.8

Doctoral theses:

  • Cristina Sánchez González. In course
  • Cristina Nuevo Tapioles. April 2019, sobresaliente cum laude. (Co-direction with Professor J.M. Cuezva)

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