B14 - The link between mitochondrial ultrastructure and innate immune response upon fumarate hydratase loss
Christian Frezza
CECAD Research Center
University Hospital Cologne
E-mail: christian.frezza@uni-koeln.de
Phone: +49 (0) 221 478 84308
Désirée Schatton
CECAD Research Center
University Hospital Cologne
E-mail: desiree.schatton@uk-koeln.de
Phone: +49 (0) 221 478 84000
For more information and contact please visit the FREZZA LAB.
Abstract
In this project we will shed light on the molecular connection between the accumulation of the metabolite fumarate caused by FH loss and the changes in mitochondrial ultrastructure and the ensuing release of mtDNA, as well as the effects of the resulting interferon response on renal cell carcinoma. We will address the main open questions in three working packages. First, we will elucidate the molecular link between accumulated fumarate and mitochondrial derived vesicle (MDV) formation. Then, we will identify molecular players of MDV formation and the interferon response and finally we will investigate the (patho)physiological consequences of the triggered innate immune response in vivo.
Project-related publications
Valcarcel-Jimenez L, Frezza C (2023). Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. Br J Cancer. 10.1038/s41416-023-02412-w. DOI: 10.1038/s41416-023-02412-w.
Zecchini V, Paupe V, Herranz-Montoya I, Janssen J, Wortel IMN, Morris JL, Ferguson A, Chowdury SR, Segarra-Mondejar M, Costa ASH, Pereira GC, Tronci L, Young T, Nikitopoulou E, Yang M, Bihary D, Caicci F, Nagashima S, Speed A, Bokea K, Baig Z, Samarajiwa S, Tran M, Mitchell T, Johnson M, Prudent J, Frezza C (2023). Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature 615:499-506. DOI: 10.1038/s41586-023-05770-w.
Hooftman A, Peace CG, Ryan DG, Day EA, Yang M, McGettrick AF, Yin M, Montano EN, Huo L, Toller-Kawahisa JE, Zecchini V, Ryan TAJ, Bolado-Carrancio A, Casey AM, Prag HA, Costa ASH, De Los Santos G, Ishimori M, Wallace DJ, Venuturupalli S, Nikitopoulou E, Frizzell N, Johansson C, Von Kriegsheim A, Murphy MP, Jefferies C, Frezza C, O'Neill LAJ (2023). Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. Nature 615:490-498. DOI: 10.1038/s41586-023-05720-6.
Valcarcel-Jimenez L, Rogerson C, Yong C, Schmidt C, Yang M, Cremades-Rodelgo M, Harle V, Offord V, Wong K, Mora A, Speed A, Caraffini V, Tran MGB, Maher ER, Stewart GD, Vanharanta S, Adams DJ, Frezza C (2022). HIRA loss transforms FH-deficient cells. Sci Adv 8:eabq8297. DOI: 10.1126/sciadv.abq8297.
Schatton D, Di Pietro G, Szczepanowska K, Veronese M, Marx MC, Braunöhler K, Barth E, Müller S, Giavalisco P, Langer T, Trifunovic A, Rugarli EI (2022). CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression. eLife 11:e74552. DOI: 10.7554/eLife.74552.