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Friday, 14th December 2018
Cell Biology and Immunology

Biogenesis and function of mitochondria and its role in pathology


Grupo-400

 


José M. Cuezva

ASciStaff

APublications

Research summary:

Mitochondria play key roles in metabolism, the execution of cell death and intracellular signaling. Consistent with the prime physiological roles of mitochondria its dysfunction is involved in the genesis and progression of ageing and of a plethora of pathologies including cancer and neurodegeneration. The mitochondrial ATP synthase is a key transducer in energy conservation and in signaling, in shaping the structure of cristae and in the execution of death. Previously, we have documented that the expression of the ATP synthase is partially repressed in human carcinomas providing a “bioenergetic signature” of disease progression. More recently, we have described that its inhibitor, the ATPase Inhibitory Factor 1 (IF1), is highly overexpressed in most prevalent carcinomas and demonstrated that it plays a prominent role in metabolic reprogramming of tumor cells and during differentiation of stem cells. Moreover, the IF1-mediated inhibition of the ATP synthase triggers a ROS signal that promotes the activation of nuclear programs aimed at cell survival. We have developed transgenic mice that conditionally express IF1 in neurons, hepatocytes, intestinal epithelium or heart and demonstrated in vivo the role of IF1 in metabolic reprograming and nuclear signaling “mitohormetic” responses, including the mechanisms by which IF1 overexpression promotes a pro-oncogenic phenotype in liver (Fig. 1). Furthermore, we have succeeded in the generation of the ATPIF1 lox/lox mice for the development of IF1-KO mice in different tissues and demonstrated that the binding of IF1 to the ATP synthase, which promotes the inhibition of the enzyme in hypoxia, cell cycle and in cancer, is regulated by the activity of a mitochondrial cAMP-dependent protein kinase (Fig. 2). Hence, IF1 is a most relevant mitochondrial protein that defines the cellular phenotype. Our main objective is to deepen into the knowledge of the cellular biology of IF1 and of its implication in cancer, neuronal function and in ageing.

figure1

Fig. 1: The overexpression of human IF1 in mouse liver increased DEN-induced hepatocarcinogenesis (Taken from Oncotarget (2016) 7,490-508).

 

figure2

Fig. 2: Phosphorylation of IF1 inactivates its inhibitory activity by preventing its binding to the ATP synthase to regulate cellular energy metabolism (Taken from Biochim. Biophys. Acta (2016) 1857,1167-1182).

 


 

Publications:

  • Esparza-Moltó PB1, Nuevo-Tapioles C, Chamorro M, Nájera L, Torresano L, Santacatterina F, Cuezva JM. Tissue-specific expression and post-transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues. FASEB J. 2018 Sep 11.
  • Santacatterina F, Torresano L, Núñez-Salgado A, Esparza-Molto PB, Olive M, Gallardo E, García-Arumi E, Blazquez A, González-Quintana A, Martín MA, Cuezva JM. Different mitochondrial genetic defects exhibit the same protein signature of metabolism in skeletal muscle of PEO and MELAS patients: A role for oxidative stress. Free Radic Biol Med. 2018 Aug 20;126:235-248.
  • Esparza-Moltó PB, Cuezva JM. The Role of Mitochondrial H(+)-ATP Synthase in Cancer. Front Oncol. 2018;8:53.
  • Goldberg J, Currais A, Prior M, Fischer W, Chiruta C, Ratliff E, Daugherty D, Dargusch R, Finley K, Esparza-Moltó PB, Cuezva JM, Maher P, Petrascheck M, Schubert D. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell. 2018 Apr;17(2).
  • 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;19:1202-1213.
  • 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;60:2052-2065.
  • Esparza-Moltó PB, Nuevo-Tapioles C, Cuezva JM. Regulation of the H(+)-ATP synthase by IF1: a role in mitohormesis. Cell Mol Life Sci. 2017;74:2151-2166.
  • Santacatterina F, Sánchez-Cenizo L, Formentini 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 ;7:490-508.
  • García-Bermúdez J, Sánchez-Aragó M, Soldevilla B, Del Arco A, Nuevo-Tapioles C, Cuezva JM. PKA Phosphorylates the ATPase Inhibitory Factor 1 and Inactivates Its Capacity to Bind and Inhibit the Mitochondrial H(+)-ATP Synthase. CellRep. 2015;12:2143-55.
  • Formentini L, Pereira MP, Sánchez-Cenizo L, Santacatterina F, Lucas JJ, Navarro C, Martínez-Serrano A, Cuezva JM. In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning. EMBO J. 2014 ;33:762-78.
  • Sánchez-Aragó M, García-Bermúdez J, Martínez-Reyes I, Santacatterina F, Cuezva JM. Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells. EMBO Rep. 2013 ;14:638-44.
  • Sánchez-Aragó M, Formentini L, Martínez-Reyes I, García-Bermudez J, Santacatterina F, Sánchez-Cenizo L, Willers IM, Aldea M, Nájera L, Juarránz A, López EC, Clofent J, Navarro C, Espinosa E, Cuezva JM. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers. Oncogenesis. 2013;2:e46.
  • Formentini L, Sánchez-Aragó M, Sánchez-Cenizo L, Cuezva JM. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell. 2012;45:731-42.
  • Ortega AD, Willers IM, Sala S, Cuezva JM. Human G3BP1 interacts with beta-F1-ATPase mRNA and inhibits its translation. J Cell Sci. 2010;123(Pt 16):2685-96.
  • Sánchez-Cenizo L, Formentini L, Aldea M, Ortega AD, García-Huerta P, Sánchez-Aragó M, Cuezva JM. Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem. 2010;285:25308-13.
  • Sánchez-Aragó M, Chamorro M, Cuezva JM. Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis. 2010;31:567-76.
  • Cuezva JM, Ortega AD, Willers I, Sánchez-Cenizo L, Aldea M, Sánchez-Aragó M. The tumor suppressor function of mitochondria: translation into the clinics. Biochim Biophys Acta. 2009;1792:1145-58.
  • López-Ríos F, Sánchez-Aragó M, García-García E, Ortega AD, Berrendero JR, Pozo-Rodríguez F, López-Encuentra A, Ballestín C, Cuezva JM. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res. 2007;67:9013-7.
  • Santamaría G, Martínez-Diez M, Fabregat I, Cuezva JM. Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase. Carcinogenesis. 2006;27:925-35.
  • Isidoro A, Casado E, Redondo A, Acebo P, Espinosa E, Alonso AM, Cejas P, Hardisson D, Fresno Vara JA, Belda-Iniesta C, González-Barón M, Cuezva JM. Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis. Carcinogenesis. 2005;26:2095-104.
  • Cuezva JM, Chen G, Alonso AM, Isidoro A, Misek DE, Hanash SM, Beer DG. The bioenergetic signature of lung adenocarcinomas is a molecular marker of cancer diagnosis and prognosis. Carcinogenesis. 2004;25:1157-63.
  • Cuezva JM, Krajewska M, de Heredia ML, Krajewski S, Santamaría G, Kim H, Zapata JM, Marusawa H, Chamorro M, Reed JC. The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res. 2002;62:6674-81.
  • de Heredia ML, Izquierdo JM, Cuezva JM. A conserved mechanism for controlling the translation of beta-F1-ATPase mRNA between the fetal liver and cancer cells. J Biol Chem. 2000;275:7430-7.
  • Izquierdo JM, Cuezva JM. Control of the translational efficiency of beta-F1-ATPase mRNA depends on the regulation of a protein that binds the 3' untranslated region of the mRNA. Mol Cell Biol. 1997;17:5255-68.
  • Lithgow T, Cuezva JM, Silver PA. Highways for protein delivery to the mitochondria. Trends Biochem Sci. 1997;22:110-3.
  • Izquierdo JM, Ricart J, Ostronoff LK, Egea G, Cuezva JM. Changing patterns of transcriptional and post-transcriptional control of beta-F1-ATPase gene expression during mitochondrial biogenesis in liver. J Biol Chem. 1995;270:10342-50.
  • Alconada A, Flores AI, Blanco L, Cuezva JM. Antibodies against F1-ATPase alpha-subunit recognize mitochondrial chaperones. Evidence for an evolutionary relationship between chaperonin and ATPase protein families. J Biol Chem. 1994;269:13670-9.
  • Luis AM, Izquierdo JM, Ostronoff LK, Salinas M, Santarén JF, Cuezva JM. Translational regulation of mitochondrial differentiation in neonatal rat liver. Specific increase in the translational efficiency of the nuclear-encoded mitochondrial beta-F1-ATPase mRNA. J Biol Chem. 1993;268:1868-75.
  • Izquierdo JM, Luis AM, Cuezva JM. Postnatal mitochondrial differentiation in rat liver. Regulation by thyroid hormones of the beta-subunit of the mitochondrial F1-ATPase complex. J Biol Chem. 1990;265:9090-7.
  • Luis AM, Alconada A, Cuezva JM. The alpha regulatory subunit of the mitochondrial F1-ATPase complex is a heat-shock protein. Identification of two highly conserved amino acid sequences among the alpha-subunits and molecular chaperones. J Biol Chem. 1990;265:7713-6.
  • Valcarce C, Navarrete RM, Encabo P, Loeches E, Satrústegui J, Cuezva JM. Postnatal development of rat liver mitochondrial functions. The roles of protein synthesis and of adenine nucleotides. J Biol Chem. 1988;263:7767-75.

 


 

Other activities:

  • We are Unit 713 of CIBERER, in the field of Mitochondrial Pathology of the CIBER de Enfermedades Raras, Instituto de Salud Carlos III.
  • We are the Research Group leading “Translation of Energy Metabolism” in the field of Cancer of the Instituto de Investigación Hospital 12 de Octubre (i+12).
  • We have coordinated the MITOLAB Consortium of the Comunidad de Madrid.
  • Organized de “MITOLAB Closing Meeting” of the Madrid I+D Program, 12-13/11/2015.

 


 

Thesis:

  • Javier García Bermúdez. 2015. "Regulación de la expresión y actividad de IF1, el inhibidor fisiológico de la H+-ATP sintasa de la mitocondria” Universidad Autónoma de Madrid. Directores: José M. Cuezva and María Sánchez-Aragó. Sobresaliente “cum laude”. Awarded “Premio Extraordinario”.
  • Fulvio Santacatterina. 2016. Metabolismo energético en patología y su traslación a la clínica”. Universidad Autónoma de Madrid. Director: José M. Cuezva. Sobresaliente “cum laude”.

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