Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects' fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects' fibroblasts with wild-type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.
Duchenne muscular dystrophy (DMD) is a devastating neuromuscular degenerative disease with no known cure to date. In recent years, the hypothesis of a "gut-muscle axis" has emerged suggesting that bidirectional communication between the gut microbiota and the muscular system regulates the muscular function and may be perturbed in several muscular disorders. In addition, the excessive consumption of sugar and of lipid-rich processed food products are factors that further aggravate the phenotype for such diseases and accelerate biological aging. However, these unhealthy microbiota profiles can be reversed by individualized dietary changes to not only alter the microbiota composition but also to reset the production of microbial metabolites known to trigger beneficial effects typically associated with prolonged health span. Two recent studies (in this issue of EMBO Mol Med) highlight the interesting potential of microbiota-informed next-generation dietary intervention programs to be considered in genetically linked muscle disorders like DMD.