2026
Cell

Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy

Authors:

Annika Zink, Dao-Fu Dai, Annika Wittich, Marie-Thérèse Henke, Giulia Pedrotti, Sonja Heiduschka, Guillem Santamaria, Tancredi Massimo Pentimalli, Christian Brueser, Sofia Notopoulou, Abdul Rahim Umar, Aleksandra Zhaivoron, Laura Petersilie, Caleb Jerred, Jesper Bergmans, Louis Anton Neu, Fabian Schumacher, Jan Keller-Findeisen, Agnieszka Rybak-Wolf, Daniel Stach, Jeanette Reinshagen, Undine Haferkamp, Kim Krieg, Andrea Zaliani, Liliya Euro, Alessia Di Donfrancesco, Chiara Santanatoglia, Enrica Cappellozza, Marta Suarez Cubero, Mario Pavez-Giani, Oleh Bakumenko, David Meierhofer, Alan Foley, Susanne Morales-Gonzalez, Isabella Tolle, Diran Herebian, Daniele Bonesso, Giulia Cecchetto Sakurako Nagumo Wong, Monica Moresco, Alessandra Maresca, Ilaria Decimo, Francesco De Sanctis, Annalisa Adamo, Merel J.W. Adjobo-Hermans, Roberto Duchi, Maria Barandalla, Marco Scaglia, Andrea Perota, Cesare Galli, Burkhard Kleuser, Lukas Cyganek, Chris Mühlhausen, Lars Schlotawa, Valeria Tiranti, Ertan Mayatepek, Ildiko Szabo, Chiara La Morgia, Thomas Klopstock Valerio Carelli, Felix Distelmaier, Andrea Rossi, Nikolaus Rajewsky, Ghanim Ullah, Stefan Jakobs, Christine R. Rose, Spyros Petrakis, Frank Edenhofer, Werner J.H. Koopman, Pawel Lisowski, Anu Suomalainen, Dario Brunetti, Antonio del Sol, Emanuela Bottani, Ole Pless, Markus Schuelke, Alessandro Prigione

Keywords:

mitochondrial diseases; Leigh syndrome; iPSCs; brain organoids; PDE5 inhibitors; sildenafil; PRKG1; high-content analysis; drug screening; drug repurposing

Abstract:

Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends lifespan and ameliorates disease phenotypes. Off-label treatment on an individual basis with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.