Phosphodiesterase type 5 inhibition as a therapeutic strategy in primary mitochondrial disease: Evidence from patient fibroblasts and clinical observations

Abstract

Primary mitochondrial diseases are a heterogeneous group of disorders caused by impaired mitochondrial respiratory chain function due to pathogenic variants in nuclear or mitochondrial DNA. These variants disrupt enzyme activity, membrane integrity, or mitochondrial genome maintenance. Phosphodiesterase type 5 (PDE5) inhibitors have recently emerged as potential modulators of mitochondrial function. Prompted by self-reported symptom improvement in an individual with mitochondrial disease taking tadalafil, we investigated the effects of PDE5 inhibitors in this context. Using high-resolution respirometry, we analyzed mitochondrial function in fibroblasts from six individuals with primary mitochondrial disease following treatment with sildenafil or tadalafil. We hypothesized that PDE5 inhibition would improve mitochondrial respiratory function and alleviate clinical symptoms. Clinical outcomes were also assessed in three individuals receiving off-label tadalafil therapy. Patient-derived fibroblasts showed elevated basal and non-mitochondrial respiration, along with increased glycolytic flux. Treatment with PDE5 inhibitors reduced proton leak-associated OCR, improved coupling efficiency, and normalized metabolic profiles. Off-label tadalafil use was associated with acute, dose-dependent, and sustained symptom improvements in all three individuals, with no adverse effects reported. In MELAS fibroblasts responses varied with m.3243 A > G heteroplasmy levels. These findings suggest PDE5 inhibitors may offer safe, accessible, and personalized therapeutic options for mitochondrial diseases, particularly those involving mitochondrial DNA pathogenic variants.