(A) Schematic overview of the “hypoxia-in-a-pill” regimen. GBT440 is an orally available activator of Hb affinity that, in theory, can reduce tissue oxygen delivery. In response to hypoxia, the body will mount a compensatory, erythroid response driven by HIF-2α, which is inhibited by PT2399. (B) Hb and (C) brain PbO₂ measurements in 8-week-old WT mice treated with vehicle, GBT440, PT2399 or the combination for 3 weeks. (D) Body weight of WT mice treated with the indicated drugs. (E) Distance traveled in 15 minutes on an open-field test of Ndufs4-KO mice treated with vehicle or the GBT440/PT2399 combination. (F) Representative T2-MRI of Ndufs4-KO mice treated with vehicle or the combination at 60 and 67 days of age. Red arrowheads, Leigh-like lesion; yellow arrowheads, hemorrhage. (G) Survival of Ndufs4-KO mice treated with vehicle, GBT440, PT2399, or a combination. Bar plots show the mean ± SD. n = group size. *P < 0.05, **P < 0.01, ***P < 0.001; 1-way ANOVA with Dunnett’s test for multiple comparisons with vehicle; t test for single comparisons of GBT440/PT2399 versus vehicle; log-rank test for survival of drug-versus vehicle–treated mice.