Journal Article

DZNE-2026-00302

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.

Zink, A. ; Dai, D.-F. ; Wittich, A. ; Henke, M.-T. ; Pedrotti, G. ; Heiduschka, S. ; Santamaria, G. ; Pentimalli, T. M. ; Brueser, C. ; Notopoulou, S. ; Umar, A. R. ; Zhaivoron, A. ; Petersilie, L. ; Jerred, C. ; Bergmans, J. ; Neu, L. A. ; Schumacher, F. ; Keller-Findeisen, J. ; Rybak-Wolf, A. ; Stach, D. ; Reinshagen, J. ; Haferkamp, U. ; Krieg, K. ; Zaliani, A. ; Euro, L. ; Di Donfrancesco, A. ; Santanatoglia, C. ; Cappellozza, E. ; Suarez Cubero, M. ; Pavez-Giani, M. ; Bakumenko, O. ; Meierhofer, D. ; Foley, A. ; Morales-Gonzalez, S. ; Tolle, I. ; Herebian, D. ; Bonesso, D. ; Cecchetto, G. ; Wong, S. N. ; Moresco, M. ; Maresca, A. ; Decimo, I. ; De Sanctis, F. ; Adamo, A. ; Adjobo-Hermans, M. J. W. ; Duchi, R. ; Barandalla, M. ; Scaglia, M. ; Perota, A. ; Galli, C. ; Kleuser, B. ; Cyganek, L. ; Mühlhausen, C. ; Schlotawa, L. ; Tiranti, V. ; Mayatepek, E. ; Szabo, I. ; La Morgia, C. ; Klopstock, T.DZNE* ; Carelli, V. ; Distelmaier, F. ; Rossi, A. ; Rajewsky, N.DZNE* ; Ullah, G. ; Jakobs, S. ; Rose, C. R. ; Petrakis, S. ; Edenhofer, F. ; Koopman, W. J. H. ; Lisowski, P. ; Suomalainen, A. ; Brunetti, D. ; Del Sol, A. ; Bottani, E. ; Pless, O. ; Schuelke, M. ; Prigione, A.

2026
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.cell.2026.02.008

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.

Keyword(s): Sildenafil Citrate: pharmacology (MeSH) ; Sildenafil Citrate: therapeutic use (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: drug effects (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; Animals (MeSH) ; Phosphodiesterase 5 Inhibitors: pharmacology (MeSH) ; Phosphodiesterase 5 Inhibitors: therapeutic use (MeSH) ; Leigh Disease: drug therapy (MeSH) ; Mice (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: metabolism (MeSH) ; Membrane Potential, Mitochondrial: drug effects (MeSH) ; Mitochondrial Diseases: drug therapy (MeSH) ; Organoids: drug effects (MeSH) ; Organoids: metabolism (MeSH) ; Leigh syndrome ; PDE5 inhibitors ; PRKG1 ; brain organoids ; drug repurposing ; drug screening ; high-content analysis ; iPSCs ; mitochondrial diseases ; sildenafil ; Sildenafil Citrate ; Phosphodiesterase 5 Inhibitors

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Berlin common (Berlin common)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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