CENTRO DE BIOLOGÍA MOLECULAR SEVERO OCHOACaptura de pantalla 2022 09 14 a las 10.27.10    

Mouse models of disease: the role of mitochondrial bioenergetics in physiopathology

Research summary:

  • Past achievements

During the past years, our research has been focused on understanding how mitochondrial energy metabolism contributes to the integration of cellular functions, leading to the onset and progression of various pathologies. Complex regulatory mechanisms enable mitochondrial metabolism to meet cellular demands, which go beyond ATP production. We have demonstrated that mitochondrial oxidative phosphorylation also plays additional roles in controlling cell immunity and inflammation (Formentini L. et al., Cell Reports, 2017, PMID: 28494869) and regulating intra- and inter-cellular oncogenic signals (Nuevo-Tapioles, C. et al., Nature Communications, 2020, PMID: 32681016). Impaired mitochondrial function also significantly affects adipose tissue and skeletal muscle lipid species and metabolism (Formentini L et al., Diabetologia, 2017, PMID: 28770317; Sanchez-Gonzalez C et al, EMBO J. 2020, PMID: 32488939). Interestingly, these metabolic disturbances impair ROS and calcium signaling, leading to profound changes in muscle structure (Sanchez-Gonzalez C et al, Cell Death and Disease 2022, PMID: 32488939), thus emerging as key hallmarks of myopathies.

  • Future plans

One of the main goals of my research line, supported by PID2019-104241RB-I00 national funding and Fundación Ramón Areces, is to further investigate mitochondrial metabolism in pathophysiology. Using two conditional and tissue-specific mouse models with impaired mitochondrial activity (dysfunctional oxidative phosphorylation mice, LowOXPHOS mice; dysfunctional fatty acid oxidation mice, LowFAO mice), my research group is elucidating how different mitochondrial dysfunctions, environmental factors, and diets impact metabolism at the cellular, tissue, and organismal levels. We aim to identify the aspects of mitochondrial activity that limit cell homeostasis and understand which products of metabolism are essential for proper organism function, as well as how cells obtain or transform them in physiological tissue environments. This knowledge is crucial for exploiting mitochondrial metabolism for therapeutic purposes.

 

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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
Civettini Linda3264648Becario Erasmus
Formentini Laura3264648lformentini(at)cbm.csic.esProfesor Contratado Doctor Universidad, GA
Salegi AnsaBeñat3264648bsalegi(at)cbm.csic.esAyudante Investigación

Relevant publications:

  • Sánchez-González C, Herrero Martín JC, Salegi Ansa B, Núñez de Arenas C, Stančič B, Pereira MP, Contreras L, Cuezva JM, Formentini L. Chronic inhibition of the mitochondrial ATP synthase in skeletal muscle triggers sarcoplasmic reticulum distress and tubular aggregates. Cell Death & Disease 2022 Jun 22;13(6):561. doi: 10.1038/s41419-022-05016-z. PMID: 35732639; PMCID: PMC9217934.

  • Sanchez-Gonzalez C., Nuevo-Tapioles C, Herrero-Martín J, Pereira MP, Cuezva JM, Formentini L* (*corresponding author). Dysfunctional muscle oxidative phosphorylation shunts BCCA catabolism onto lipogenesis in skeletal muscle. EMBO J. 2020. e103812 CLAVE: A. Impact Factor: 11,2

  • Nuevo-Tapioles C, Santacatterina F, Stamatakis K, Nuñez de Arenas C, Gomez de Cedron, M, Formentini L and Cuezva JM. Coordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth. Nat Comm. 2020. 11:3606. CLAVE: A. Impact Factor: 12,1

  • Formentini L*(*: corresponding author), 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 CLAVE: A. Impact factor: 7,5

  • 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. CLAVE: A. Impact factor: 8.2

  • 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. CLAVE: A. Impact factor: 10.4

  • 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.  CLAVE: A. ImpactFactor: 15.4.

Doctoral theses:

1) Cristina Nuevo Tapioles:
FPI-Reference: BES-2014-068929
Associated Project: SAF2013-41945-R, PI: J.M Cuezva
PhD-thesis: “Regulación de la OXPHOS mediada por IF1 y su papel como diana terapéutica en cáncer”.
Thesis Defense: April 26th, 2019, UAM. Sobresaliente “cum laude”.
PhD director: Laura Formentini and J.M Cuezva

2) Cristina Sanchez Gonzalez:
FPI-Reference: BES-2017-079909
Associated Project: SAF2016-76028-R, PI: Laura Formentini
PhD-Thesis: “Papel de la bioenergética mitocondrial sobre el metabolismo del músculo esquelético durante el ejercicio y en patología “.
Thesis Defense: February 8th, 2022, UAM. Sobresaliente “cum laude”.
PhD director: Laura Formentini

3) Juan Cruz Herrero Martín (direction)
Contract funded by PID2019-104241RB-I00 project, PI: Laura Formentini
PhD-Thesis: “Papel de las deshidrogenasas FAD dependientes en la fisiopatología del musculo esquelético”
Thesis Defense: July 6th, 2022, UAM. Sobresaliente “cum laude”.
PhD director: Laura Formentini

4) Beñat Salegi Ansa (direction)
Contract funded by PID2019-104241RB-I00 project, PI: Laura Formentini
In progress.

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