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Future studies are required to address these aspects in the context of sildenafil treatment in mitochondrial diseases. Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Alessandro Prigione ([email protected]). Information requests regarding Leigh syndrome patients and their treatment should be directed to the lead clinical scientist, Markus Schuelke ([email protected]). There are restrictions on the availability of patient-derived iPSCs used in this study due to our ethical approval, which does not support sharing with third parties without a specific amendment and does not allow performing genomic studies, in order to respect the European privacy protection law. Raw and processed RNA-seq data are deposited in the NCBI Gene Expression Omnibus (GEO) or Sequence Read Archive (SRA): bulk RNA-seq NPC dataset at GEO: GSE292178; bulk RNA-seq brain organoids dataset at SRA BioProject: and snRNA-seq brain organoids dataset at GEO: GSE293573.

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The metabolomics NPC dataset is deposited in the MassIVE repository at MassIVE: Codes to reproduce our snRNA-seq results are available at: All original code is available in this paper’s STAR Methods. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. We acknowledge financial support from the European Joint Programme for Rare Diseases (EJPRD) (CureMILS to A. Prigione, sildenafil 25mg tablets O.P., W.J.H.K., A.D.-S., P.L., E.B., A.S., and F.E. ); the Austrian Science Fund (FWF) (10.55776/I5184 and 10.55776/F78 to F.E.

ERK and calcineurin were activated in the RV as well as in the LV, and were inhibited by sildenafil treatment

); the United Mitochondrial Disease Foundation (UMDF) and the Leigh Syndrome International Consortium (LSIC) (to A. Prigione and D.-F.D. ); the foundations People Against Leigh Syndrome (PALS), Mito Foundation, Foundation Maladies Rares and Association (AMMi), Cure Mito and Cure ATP6, and Mitocon Italy (to A. Prigione); MitoHelp and the Eva Luise Köhler Foundation (to A. Prigione and M. Prigione, M.-T.H., G.P., S.H., and M.

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Schuelke; funding acquisition, A. Prigione, D.

Side Effect	Severity	Notes
Headache	Common	Usually mild
Flushing	Common	Transient
Dizziness	Common	Particularly when standing up quickly
Vision disturbances	Less common	Temporary, includes blue tint or blurred vision
Priapism	Rare	Needs urgent medical attention

Brunetti, A.d.S., O.P., W.J.H.K., P.L., A.S., F.E., E.B., M. Schuelke, and C.R.R. A. Prigione and M.

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Schuelke); KIAT 2410008128 and NIH DK133118 (to D.-F.D. ); North Rhine-Westphalia and the European Union (IN-SU-3-001 to A.R. ); the European Union (FETPROACT-2018-2020 HERMES 824164 to I.D. ); the National Recovery and Resilience Plan (NRRP) (Mission 4, Component 2, Investment 1.1, Call for Tender No. 104 on February 2, 2022, by the Italian Ministry of University and Research, sildenafil 100mg blue pill funded by the European Union – NextGeneration EU, project CUP B53D23018710001, Grant Assignment Decree no.

RV remained apparently normal by two-day LV pressure overload (TAC), with mild LV hypertrophy that was inhibited by sildenafil

1110, adopted on July 20, 2023, by MUR) (to E.B. ; GMR23T2152 to D. Brunetti); the Italian Foundation A.M.Me.C. ); Leibniz Competition (SAW) Cooperative Excellence Project (K642/2024 to A.R. V.T., C.L.M., V.C., and M.

In vivo hemodynamics

Schuelke are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). Part of the work was performed at the Center for the Study of Mitochondrial Pediatric Diseases, funded by the Mariani Foundation, Italy, at Fondazione IRCCS Istituto Neurologico “Carlo Besta.” During this study, A.S. was funded by the Research Council of Finland, the Jane and Aatos Erkko Foundation, the PolG Foundation, and the Sigrid Jusélius Foundation. We acknowledge the Center for Advanced Imaging (CAi) at HHU for providing access to the Revvity Operetta CLS. The graphical abstract was created with BioRender: Conceptualization, A. Schuelke filed patent applications for sildenafil in the treatment of CIV and CV defects and obtained Orphan Drug Designation (ODD) for sildenafil in Leigh syndrome from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) (EU/3/23/2831). MT-ATP6 mutant iPSC lines were previously derived from three patients with m.9185T>C variant (ATP61_1: HHUi001-A; ATP6_2: HHUi002-A; ATP6_3: HHUi003-C), one patient with m.8993T>C variant (ATP6_4: MDCi008-A), two patients with m.8993T>G variant (ATP6_5: MDCi009-A; ATP6_6: MDCi010-A), and one patient with m.9176T>G variant (ATP6_7: BIHi267-B) (Figure S10H).27,33,34,35 Genotyping of the lines was carried out by Sanger sequencing (Figure S1A). SURF1 mutant iPSC isogenic lines (SURF1_1: HMGUi001-A-64) and NDUFS4 mutant iPSC isogenic lines (NDUFS4_1: HVRDi004-B-6; NDUFS4_2: HVRDi004-B-7) were previously derived (Figure S10H).25,89 Among healthy control iPSCs (Figure S10H), CTRL_1, (HMGUi001-A), CTRL_2 (HHUUKDi009-A), CTRL_4 (BIHi269-B), CTRL_7 (BIHi266-A), and CTRL_9 (UMGi014-C) were previously described,27,33,128,129 CTRL_3 (CRMi003-A)126 was purchased from RUCDR Infinite Biologics, CTRL_5 (HVRDi004-B, PGP1)127 was purchased from Synthego, CTRL_6 (IUFi004-A, iPS12)130 was purchased from Cell Applications, and CTRL_8 (WISCi004-B)131 was purchased from WiCell. We cultured all iPSC lines on Matrigel (Corning)-coated plates using StemMACS iPS-Brew XF medium, supplemented with MycoZap (Lonza).

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CTRL_8 and ATP6_2 iPSCs were cultured in mTeSR Plus Medium (STEMCELL Technologies) prior to BCEC differentiation.

Medication Class	Interaction Effect	Notes
Nitrates	Severe hypotension risk	Do not combine
Alpha-blockers	Potentiates blood pressure lowering	Use with caution
CYP3A4 inhibitors	Increases sildenafil levels	Adjust dosage accordingly
Other PDE5 inhibitors	Increased risk of side effects	Usually not combined

Information on sex and age of the individuals from which the iPSCs were derived is provided in Figure S10H.

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We cultivated all iPSCs in a humidified atmosphere of 5 % CO2 at 37 °C and 5 % oxygen.

• Storage of sildenafil should be in a cool, dry place away from direct sunlight.
• Common side effects include dizziness, upset stomach, or vision changes.
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iPSCs were split at 70-80 % confluence with 0.5 μM EDTA (Invitrogen) in 1 x PBA (Gibco). We added 10 μM ROCK inhibitor (Enzo Biochem Inc) after splitting to promote survival.

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Prigione, M. Schuelke, O.P., D.-F.D., E.B., W.J.H.K., A.d.S., A.S., P.L., and F.E. ; writing – original draft, A. Prigione; writing – review & editing, A. Prigione, O.P., M. Cultures were routinely monitored for mycoplasma contamination by PCR using nine primers to amplify the six most common mycoplasma strains (Table S5). The positive control and internal contro were kindly provided by Dr. Cord Uphoff (DZMS, Germany). We monitored the identity of iPSCs using STR analysis, which was performed by the Forensic Department of the University Hospital Düsseldorf (Dr. Petra Böhme); 21 microsatellite loci were amplified using PCR and tagged products were analyzed using GeneMapper ID v.3.2.1 (Applied Biosystems).

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Schuelke, D.-F.D., E.B., and C.R.R. ; supervision, A. Prigione, O.P., C.R.R., I.S., M.J.W.A.-H., E.M., S.J., G.U., S.P., W.J.H.K., A.S., F.E., women sildenafil E.B., M. Schuelke, L.C., V.C., S.J., A.d.S., and D. Brunetti; visualization, A. The use of iPSCs in pseudoanonymized manner was approved by the local ethic committees of Charité-Universitätsmedizin Berlin (EA2/131/13 and EA2/107/14) and Heinrich Heine University Düsseldorf (Study number 2020-967_5).

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Germline Ndufs4 KO mice were obtained from the University of Washington.132 All mice were on the C57/BL6/J background and were fed the regular diet from Harlan Teklad.132 Sildenafil citrate treatment was initiated soon after weaning and genotyping, between day 25-30 of age.

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Modulation of BKCa channels has been implicated in the sildenafil effect in other disease contexts77,78 and neuronal calcium signaling can be mediated by PRKG1.111,112 However, because PRKG1 protein levels were not fully normalized in all LS models, it is possible that sildenafil might enhance PRKG1 enzymatic activity rather than its protein abundance.56 In fact, continuous application of the cGMP analog 8-Br-cGMP can reduce PRKG1 expression.113 Further dissection of this pathway is required. Whether the restorative effects of sildenafil seen in LS are linked to its vasodilatory mechanisms32 remains to be studied. The increase in blood flow and oxygen delivery to muscle and brain tissue may potentially contribute to beneficial metabolic effects. Sildenafil led to vascular and metabolic improvements in individuals with AD114 and in subjects with vascular cognitive impairment.115 The effect of sildenafil on the vasculature32 and the beneficial consequences of hypoxia seen in animal models of LS22,23 might indicate that modulation of brain vascularization and associated oxygenation116 could represent important therapeutic targets in LS. Our findings underscore the power of conducting drug discovery studies driven by iPSC models.

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Similar strategies could be applied to other neurological diseases for which effective model systems are lacking. Considering that mitochondria play a crucial role in cellular health and brain function and homeostasis,117,118,119 understanding the potential effects of PDE5i in mitochondrial diseases may also have important implications in the context of common aging-related neurological disorders. We reported clinical effects observed in a small cohort of mitochondrial disease patients. It is imperative that the safety and efficacy of sildenafil in patients with LS be assessed in a larger, double-blind, randomized, placebo-controlled trial. High sildenafil dosages were associated with toxicity in LS cardiomyocytes and microhemorrhages in newborn LS pigs.

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Although the doses that we used in LS patients have been found safe for neonatal encephalopathy,120,121 particular precautions should be taken in infants due to the low sildenafil clearance in postnatal age that leads to longer half-lives in neonates compared with adults.122 Sildenafil dosage should therefore be carefully monitored in treated children. Other more potent PDE5i, such as vardenafil (IC50 = 0.091 ± 0.031 nM) and tadalafil (IC50 = 1.8 ± 0.4 nM),123 could be considered as alternatives to sildenafil in patients with mitochondrial disorders.124 The predictions of the mathematical model and the role of mitochondrial calcium fluxes, including the mitochondrial calcium uniporter and other ion channels that could be directly modified by cGMP or PRKG1, warrant further investigation to elucidate the effects of sildenafil in neural cells. We identified here putative sildenafil-responsive genes, but additional work is needed to dissect their biological role in LS. Besides experiments in pigs, which were carried out only in male animals, both sexes were investigated in all other experiments in mice and iPSCs, as well as in treatments on an individual basis. Nonetheless, we did not assess the influence of sex or gender on disease phenotypes and treatment outcomes.