Modulazione del metabolismo neonatale nel trattamento della sindrome di Leigh: valutazione dell’efficacia in un modello suino SURF1KO

Leigh Syndrome (LS) is a fatal early-onset mitochondrial encephalopathy most frequently caused by mutations in SURF1, resulting in cytochrome c oxidase (Complex IV) deficiency and systemic oxidative phosphorylation (OXPHOS) failure. Due to the lack of effective therapies and the limited translational value of small-animal models, the SURF1 knockout (SURF1KO) pig provides a clinically relevant large-animal platform that closely mirrors the human disorder. This study evaluates the therapeutic potential of neonatal metabolic intervention using PD-0E7, a novel supplementary diet formulation designed to enhance bioenergetic capacity and anabolic signalling. Newborn SURF1KO piglets received oral PD-0E7 from birth at a neonate-tolerated dosage (0.5 g/kg/day). Whereas all untreated SURF1KO piglets died within 24–48 hours, PD-0E7 administration significantly prolonged survival to 5–9 weeks. Treated animals displayed restored thermoregulation, improved feeding behaviour, enhanced spontaneous motor activity, and delayed onset of neuromuscular decline. Molecular and biochemical analyses of brain and skeletal muscle showed that PD-0E7 effectively mitigated OXPHOS dysfunction, normalizing AMPK–mTOR–PGC-1α signalling, promoting recovery of mitochondrial and neuronal markers, and moderating maladaptive mitochondrial DNA dysregulation. Importantly, Complex IV activity in treated SURF1KO piglets was restored toward physiological levels, overcoming the severe enzymatic deficit observed in neonatal knockouts and contributing to improved metabolic stability. These adjustments aligned with widespread transcriptional and metabolic rebalancing, indicating a qualitative enhancement of mitochondrial function, redox homeostasis, and developmental progression. Together, these findings demonstrate that early-life metabolic support can markedly alter the trajectory of SURF1-related mitochondrial disease, transforming an otherwise lethal neonatal phenotype into several weeks of functional survival. PD-0E7 does not correct the underlying structural COX defect but reinforces parallel energetic pathways, stabilizes organelle quality, and supports neurodevelopment and myogenesis. This work establishes proof of concept for neonatal metabolic therapy as a promising strategy for congenital mitochondrial disorders and underscores the value of the SURF1KO pig as a robust preclinical model for testing metabolic, genetic, and combined therapeutic approaches.