Lahoz, A. (Agustín)

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    Mild muscle mitochondrial fusion distress extends drosophila lifespan through an early and systemic metabolome reorganization
    (2021) Roca, M. (Marta); Pineda-Lucena, A. (Antonio); Palomino-Schatzlein, M. (Martina); López-del-Amo, V. (Víctor); Lahoz, A. (Agustín); Galindo, M.I. (Máximo Ibo); Tapia, A. (Andrea)
    In a global aging population, it is important to understand the factors affecting systemic aging and lifespan. Mitohormesis, an adaptive response caused by different insults affecting the mitochondrial network, triggers a response from the nuclear genome inducing several pathways that promote longevity and metabolic health. Understanding the role of mitochondrial function during the aging process could help biomarker identification and the development of novel strategies for healthy aging. Herein, we interfered the muscle expression of the Drosophila genes Marf and Opa1, two genes that encode for proteins promoting mitochondrial fusion, orthologues of human MFN2 and OPA1. Silencing of Marf and Opa1 in muscle increases lifespan, improves locomotor capacities in the long term, and maintains muscular integrity. A metabolomic analysis revealed that muscle down-regulation of Marf and Opa1 promotes a non-autonomous systemic metabolome reorganization, mainly affecting metabolites involved in the energetic homeostasis: carbohydrates, lipids and aminoacids. Interestingly, the differences are consistently more evident in younger flies, implying that there may exist an anticipative adaptation mediating the protective changes at the older age. We demonstrate that mild mitochondrial muscle disturbance plays an important role in Drosophila fitness and reveals metabolic connections between tissues. This study opens new avenues to explore the link of mitochondrial dynamics and inter-organ communication, as well as their relationship with muscle-related pathologies, or in which muscle aging is a risk factor for their appearance. Our results suggest that early intervention in muscle may prevent sarcopenia and promote healthy aging.
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    Identification of novel synthetic lethal vulnerability in non small cell lung cancer by co targeting TMPRSS4 and DDR1
    (Springer Science and Business Media LLC, 2019) Pajares, M.J. (María José); Expósito, F. (Francisco); Pio, R. (Rubén); Sainz, C. (Cristina); Jantus-Lewintre, E. (Eloisa); Camps, C. (Carlos); Montuenga-Badia, L.M. (Luis M.); Villalba-Esparza, M. (María); Guruceaga, E. (Elizabeth); López-López, R. (Rafael); Redrado, M. (Miriam); Valencia, K. (Karmele); Redín, E. (Esther); Lahoz, A. (Agustín); Andrea, C.E. (Carlos Eduardo) de; Calvo-González, A. (Alfonso); Sandoval, J. (Juan); Cirauqui, C. (Cristina); Hervas, D. (D.); Diaz-Lagares, A. (Ángel)
    Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4.