Grouped but not unified: mechanistic diversity in mitochondrial skeletal disorders.

Mitochondrial disease is a term assigned to a diverse group of genetic disorders caused by impaired mitochondrial function, resulting in defective oxidative phosphorylation and ATP synthesis, with clinical manifestations that affect primarily energy-demanding tissues such as the brain and muscle. However, a subset of these conditions is characterized by prominent primary skeletal manifestations and has been designated Mitochondrial Skeletal disorders (MSDs). Since the initial review of MSDs in 2020, the number of genes in this category has expanded considerably, based on the updated Nosology of Genetic Skeletal disorders (2023) and MitoCarta3.0 (2021). In this review, we evaluate the clinical, genetic and functional evidence supporting the inclusion of the new genes and revisit the question of a shared mechanistic basis underlying this growing subgroup. Clinically, MSDs display pleiotropic and variable phenotypes, including dysplasia, craniofacial abnormalities and growth restriction. Functionally, the implicated proteins perform diverse essential roles in the mitochondria, extending beyond protein homeostasis to include maintenance of mtDNA integrity, mitochondrial metabolism, and membrane dynamics and composition. We hypothesize that these primary mitochondrial defects converge on the downstream activation of mitochondria-driven inflammatory pathways, disrupting osteogenic differentiation and bone formation through key signaling pathways (Wnt and Hedgehog), and transcription factors (RUNX2). However, consolidating this hypothesis will require deeper mechanistic studies using in vivo models, perturbation studies and multi-omic integration, ultimately enabling a more informed path towards the development of targeted therapeutic interventions.